US20230167440A1

US20230167440A1 - Method of stimulating proliferation of a cell

Info

Publication number: US20230167440A1
Application number: US17/823,839
Authority: US
Inventors: Torsten Wuestefeld; Viktoriia IAKOVLEVA
Original assignee: Agency for Science Technology and Research Singapore
Current assignee: Agency for Science Technology and Research Singapore
Priority date: 2020-07-30
Filing date: 2022-08-31
Publication date: 2023-06-01
Also published as: JP2023536814A; EP4107270A1; US12421515B2; CN116261461A; US20220364089A1; CA3187212A1; EP4107270A4; WO2022025827A1; AU2021315341A1; KR20230049661A

Abstract

Methods of treating and preventing diseases associated with fibrosis are disclosed, as well as agents for use in such methods. The methods comprise inhibiting at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. In one embodiment, the disease is a liver disease or condition. Also disclosed are methods of promoting regeneration of cells, such as hepatocytes.

Description

This application is a continuation of U.S. application Ser. No. 17/731,259, filed on 27 Apr. 2022, which is a continuation of International Application No. PCT/SG2021/050443, filed on 30 Jul. 2021, which claims priority from SG 10202007297P filed 30 Jul. 2020, the contents and elements of which are herein incorporated by reference for all purposes.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING SUBMITTED IN XML FORMAT

The Sequence Listing written in file 109046-1326735-SeqListing.xml created on Aug. 29, 2022, 9,219,798 bytes, in accordance with 37 C.F.R. §§ 1.831-1.835, is hereby incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present disclosure relates generally to the field of regenerative therapy. In particular, the specification teaches a method of stimulating or increasing proliferation and/or regeneration of a cell in a subject, comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration to stimulate or increase proliferation of the cell in the subject.

BACKGROUND

The rising incidence of acute and chronic liver failure, which causes more than 1.3 million deaths per year worldwide (World Health Organization, 2018), represents a major global health concern. The main underlying causes of end-stage liver disease are hepatitis virus infections (especially hepatitis B and C), drug- and alcohol-induced liver damage, and non-alcoholic fatty liver disease (NAFLD; associated with obesity and progressing to non-alcoholic steatohepatitis (NASH)). Asia has an especially high burden of hepatitis virus infections (WHO), and an increased incidence of NAFLD. Despite advances in the prevention and treatment of viral hepatitis (hepatitis B vaccination and hepatitis C combination therapies) the number of people with end-stage liver disease is expected to rise, mainly fueled by the obesity epidemic and aging societies.
Currently, the only curative treatment for end-stage liver disease is liver transplantation. However, donor organs are limited, and end-stage liver disease patients may also experience complications that render them unfit for major surgery. Therefore, alternative strategies to hold off or reverse end-stage liver disease are being pursued. These include cell transplantation, artificial liver devices, and enhancing the organ's endogenous regenerative capacity.
The liver is the only visceral organ that possesses the remarkable capacity to regenerate. It is known that as little as 25% of the original liver mass can regenerate back to its full size. Adult hepatocytes are long-lived and normally do not undergo cell division (Go). However, upon liver damage, they have the ability to enter the cell cycle and proliferate. Once cell proliferation is completed, the newly divided cells undergo restructuring, and other regeneration-related processes such as angiogenesis and reformation of extracellular matrix to complete the regeneration process.
Despite this amazing ability, the regenerative capacity of the liver seems limited, especially under chronic damaging conditions. The ability of the liver to regenerate is central to liver homeostasis. Because the liver is the main site of drug detoxification, it is exposed to many chemicals in the body which may potentially induce cell death and injury. Furthermore, through the enterohepatic circulation, it is exposed to microbiota related metabolites. The liver can regenerate damaged tissue rapidly thereby preventing functional failure. Liver regeneration is also critical for patients with partial removal of the liver due to tumor resection or living-donor transplantation.
In the last three decades, scientists have gained a better understanding of the process of liver regeneration. For example, the cytokines IL6 and TNFα prime the hepatocyte to enter the cell cycle and mitogens such as HGF and EGF are important for driving proliferation. However, the process of promoting the regenerative process is not well understood. Importantly, not only liver intrinsic signals are involved in the regenerative response but also signals from distant organs.
Many different processes are involved to modify the regenerative response, including nutrients, oxygen level and others. Importantly, the complex liver architecture and especially the interaction with other organs cannot be perfectly simulated in vitro and therefore in vivo experiments are essential. The disadvantage of in vivo models is in their limited potential for high throughput drug discovery pipelines, especially compound screens.
Accordingly, there is a need to overcome, or at least to alleviate, one or more of the above-mentioned problems.

SUMMARY OF THE INVENTION

The present invention concerns the treatment and/or prevention of disease through inhibition of genes and/or proteins identified to be upregulated in profibrotic processes. Inhibition of such genes/proteins has protective and regenerative effects.
The present disclosure provides a method of treating or preventing a disease associated with fibrosis, comprising inhibiting at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Also provided is a method of treating or preventing a disease associated with fibrosis, comprising administering a therapeutically or prophylactically effective amount of an inhibitor of at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to a subject.
Also provided is an inhibitor of at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB for use in a method of treating or preventing a disease associated with fibrosis.
Also provided is the use of an inhibitor of at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in the manufacture of a medicament for use in a method of treating or preventing a disease associated with fibrosis.
In some embodiments, the disease is a liver disease or condition.
In some embodiments, the disease or condition is selected from: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, mild liver fibrosis, advanced liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (ALFD), alcohol-related liver disease (ARLD), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), hepatitis, liver damage, liver injury, liver failure, metabolic syndrome, obesity, diabetes mellitus, end-stage liver disease, inflammation of the liver, lobular inflammation, and/or hepatocellular carcinoma (HCC).
In some embodiments, the inhibitor is selected from a nucleic acid, peptide, antibody, antigen-binding molecule or small molecule inhibitor. In some embodiments, the inhibitor is capable of binding to a polypeptide according to any one or more of SEQ ID NO: 7156 to 7178, or to a mRNA according to any one of SEQ ID NO: 7179 to 7195.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid having at least 75% sequence identity to any one of SEQ ID NOs: 7179 to 7195, or a portion thereof, or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NOs: 7179 to 7195, or a portion thereof.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 1 to 7155, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NOs: 1 to 7155.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 6, 7, 457 to 1482, 7095, 7096, 7109 to 7114, 7130 to 7140, 7144, 7145, 7149, 7150, 7154, and/or 7155, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 6, 7, 457 to 1482, 7095, 7096, 7109 to 7114, 7130 to 7140, 7144, 7145, 7149, 7150, 7154, and/or 7155, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of ITFG1.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 1, 2, 14 to 347, 7092, 7093, 7097 to 7102, 7115 to 7120, 7141, 7142, 7146, 7147, 7151, and/or 7152, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 1, 2, 14 to 347, 7092, 7093, 7097 to 7102, 7115 to 7120, 7141, 7142, 7146, 7147, 7151, and/or 7152, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of MFAP4.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 3 to 5, 348 to 456, 7094, 7103 to 7108, 7121 to 7129, 7143, 7148, and/or 7153, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 3 to 5, 348 to 456, 7094, 7103 to 7108, 7121 to 7129, 7143, 7148, and/or 7153, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of GRHPR.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 1483 to 2208, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 1483 to 2208, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of ABCC4.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 2209 to 5060, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 2209 to 5060, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of PAK3.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5061 to 5389, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5061 to 5389, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of TRNP1.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5390 to 5966, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5390 to 5966, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of APLN.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5967 to 6974, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5967 to 6974, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of KIF20A.
In some embodiments, the inhibitor is an inhibitory nucleic acid comprising or encoding antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 6975 to 7091, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 6975 to 7091, and optionally wherein the antisense nucleic acid is capable of reducing gene and/or protein expression of LTB.
In some embodiments, the inhibitory nucleic acid comprises: (i) nucleic acid comprising the nucleotide sequence of one of SEQ ID NO: 1 to 7096 or 7146 to 7150, or a nucleotide sequence having at least 75% sequence identity to one of SEQ ID NO: 1 to 7096 or 7146 to 7150; and (ii) nucleic acid comprising a nucleotide sequence having the reverse complement of the nucleotide sequence of (i), or having at least 75% sequence identity to the reverse complement of the nucleotide sequence of (i).
In some embodiments, the inhibitory nucleic acid comprises one or more modified nucleotides selected from: 2′-O-methyluridine-3′-phosphate, 2′-O-methyladenosine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methyluridine-3′-phosphorothioate, 2′-O-methyladenosine-3′-phosphorothioate, 2′-O-methylguanosine-3′-phosphorothioate, 2′-O-methylcytidine-3′-phosphorothioate, 2′-fluorouridine-3′-phosphate, 2′-fluoroadenosine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluorocytidine-3′-phosphorothioate, 2′-fluoroguanosine-3′-phosphorothioate, 2′-fluoroadenosine-3′-phosphorothioate, and 2′-fluorouridine-3′-phosphorothioate.
In some embodiments, the inhibitory nucleic acid comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in one of SEQ ID NO: 7146 to 7150; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in one of SEQ ID NO: 7151 to 7155.
In some embodiments, the inhibitor comprises a moiety facilitating uptake of the inhibitory nucleic acid by hepatocytes. In some embodiments, the nucleic acid inhibitor is an antisense nucleic acid, siRNA, or shRNA.
In some embodiments, the method comprises administering the inhibitor to a subject in which expression and/or activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB is upregulated.
Also provided is an inhibitory nucleic acid for reducing gene and/or protein expression of ITFG1, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7182, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7182, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 6, 7, 457 to 1482, 7095, 7096, 7109 to 7114, 7130 to 7140, 7144, 7145, 7149, 7150, 7154, and/or 7155, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 6, 7, 457 to 1482, 7095, 7096, 7109 to 7114, 7130 to 7140, 7144, 7145, 7149, 7150, 7154, and/or 7155.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of MFAP4, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7179 or 7180, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7179 or 7180, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 1, 2, 14 to 347, 7092, 7093, 7097 to 7102, 7115 to 7120, 7141, 7142, 7146, 7147, 7151, and/or 7152, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 1, 2, 14 to 347, 7092, 7093, 7097 to 7102, 7115 to 7120, 7141, 7142, 7146, 7147, 7151, and/or 7152.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of GRHPR, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7181, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7181, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 3 to 5, 348 to 456, 7094, 7103 to 7108, 7121 to 7129, 7143, 7148, and/or 7153, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 3 to 5, 348 to 456, 7094, 7103 to 7108, 7121 to 7129, 7143, 7148, and/or 7153.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of ABCC4, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to any one of SEQ ID NO: 7183 to 7186, or a portion thereof, or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 7183 to 7186, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 1483 to 2208, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 1483 to 2208.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of PAK3, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to any one of SEQ ID NO: 7187 to 7190, or a portion thereof, or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 7187 to 7190, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 2209 to 5060, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 2209 to 5060.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of TRNP1, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7191, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7191, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5061 to 5389, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5061 to 5389.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of APLN, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7192, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7192, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5390 to 5966, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5390 to 5966.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of KIF20A, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7193, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7193, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 5967 to 6974, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 5967 to 6974.
Provided is an inhibitory nucleic acid for reducing gene and/or protein expression of LTB, wherein the nucleic acid comprises or encodes antisense nucleic acid having at least 75% sequence identity to SEQ ID NO: 7194 or 7195, or a portion thereof, or having at least 75% sequence identity to the reverse complement of SEQ ID NO: 7194 or 7195, or a portion thereof.
In some embodiments, the inhibitory nucleic acid comprises or encodes antisense nucleic acid comprising or consisting of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NO: 6975 to 7091, and/or having at least 75% sequence identity to the reverse complement of any one of SEQ ID NO: 6975 to 7091.
Also provided is an inhibitory nucleic acid comprising (i) nucleic acid comprising the nucleotide sequence shown in one of SEQ ID NO: 7092 to 7096; and (ii) nucleic acid comprising the nucleotide sequence shown in one of SEQ ID NO: 7141 to 7145.
In some embodiments, the inhibitory nucleic acid comprises one or more modified nucleotides selected from: 2′-O-methyluridine-3′-phosphate, 2′-O-methyladenosine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methyluridine-3′-phosphorothioate, 2′-O-methyladenosine-3′-phosphorothioate, 2′-O-methylguanosine-3′-phosphorothioate, 2′-O-methylcytidine-3′-phosphorothioate, 2′-fluorouridine-3′-phosphate, 2′-fluoroadenosine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluorocytidine-3′-phosphorothioate, 2′-fluoroguanosine-3′-phosphorothioate, 2′-fluoroadenosine-3′-phosphorothioate, and 2′-fluorouridine-3′-phosphorothioate.
Also provided is inhibitory nucleic acid comprising (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in one of SEQ ID NO: 7146 to 7150; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in one of SEQ ID NO: 7151 to 7155.
In some embodiments, the inhibitory nucleic acid further comprises a moiety facilitating uptake of the inhibitory nucleic acid by hepatocytes. In some embodiments, the inhibitory nucleic acid is an antisense nucleic acid, siRNA or shRNA.
The present disclosure also provides a nucleic acid, optionally isolated, encoding an inhibitory nucleic acid according to the present disclosure.
The present disclosure also provides an expression vector, comprising a nucleic acid according to the present disclosure.
The present disclosure also provides a composition comprising an inhibitory nucleic acid, a nucleic acid, or an expression vector according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
The present disclosure also provides a cell comprising an inhibitory nucleic acid, a nucleic acid, or an expression vector according to the present disclosure.
The present disclosure also provides a method of treating or preventing a disease according to the present disclosure, comprising administering a therapeutically or prophylactically effective amount of an inhibitor, an inhibitory nucleic acid, a nucleic acid, an expression vector, a composition, or a cell according to the present disclosure to a subject.
The present disclosure also provides an inhibitor, an inhibitory nucleic acid, a nucleic acid, an expression vector, a composition, or a cell according to the present disclosure for use in therapy. In some embodiments, the inhibitor, inhibitory nucleic acid, nucleic acid, expression vector, composition, or cell is provided for use in a method of treating or preventing a disease, e.g. a disease according to the present disclosure.
The present disclosure also provides the use of an inhibitor, an inhibitory nucleic acid, a nucleic acid, an expression vector, a composition, or a cell according to the present disclosure in the manufacture of a medicament for use in a method of treating or preventing a disease, e.g. a disease according to the present disclosure.
Also disclosed is an in vitro or in vivo method for reducing gene and/or protein expression of one or more of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell, comprising introducing an inhibitory nucleic acid, a nucleic acid, or an expression vector according to the present disclosure into a cell.
Also disclosed is a method of regenerating liver tissue in vitro or in vivo, the method comprising inhibiting at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell of the tissue.
Also disclosed is a method of proliferating/expanding a hepatocyte in vitro or in vivo, the method comprising inhibiting at least one of ITFG1, MFAP4, GRHPR, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in the hepatocyte.
In some embodiments, a method disclosed herein comprises introducing an inhibitory nucleic acid, a nucleic acid, or an expression vector according to the present disclosure into a cell, e.g. a cell of the tissue or a hepatocyte.
Disclosed herein is a method of stimulating or increasing proliferation and/or regeneration of a cell in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to stimulate or increase proliferation and/or regeneration of the cell in the subject.
Disclosed herein is a method of enhancing cell function in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell function in the subject.
Disclosed herein is a method of enhancing cell viability in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell viability in the subject.
Disclosed herein is a method of treating a liver condition or disease in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to treat the liver condition or disease in the subject.
Disclosed herein is a method of protecting a subject from liver damage, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to protect the subject from liver damage.
Disclosed herein is a method of detecting a liver condition or disease in a subject, the method comprising detecting in a sample the level of one or more biomarkers associated with organ regeneration, wherein a change in the level of the one or more biomarkers as compared to a reference indicates that the subject is suffering from a liver condition or disease.
Disclosed herein is an inhibitor of a gene or corresponding gene product associated with organ regeneration for use in preventing or treating a liver condition or disease in the subject.
Disclosed herein is the use of an inhibitor of a gene or corresponding gene product associated with organ regeneration in the manufacture of a medicament for preventing or treating a liver condition or disease in the subject.
The methods disclosed herein may employ any suitable inhibitor. In some embodiments, the inhibitor is an inhibitor according to the present disclosure.
Disclosed herein is a nucleic acid inhibitor consisting, comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in any of Tables 1-14 or an RNAi agent that hybridizes to the complement of an RNA sequence listed in any of Tables 1-14 under stringency conditions.
Disclosed herein is a method of screening for an inhibitor of a gene or corresponding gene product associated with organ regeneration by: a) contacting the gene or corresponding gene product with a chemical compound library, and b) identifying a chemical compound within the library that is binds to the gene or corresponding gene product to inhibit the expression or function of the gene or corresponding gene product.
The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

DETAILED DESCRIPTION

The present invention relates to the identification of proteins that are involved in the development of liver disease and/or are detrimental to liver regeneration after injury, and targeting such proteins to treat liver diseases.
Without being bound by theory, the inventors have used an unbiased in vivo functional genetic screen to identify new therapeutic targets that are upregulated in liver diseases and conditions associated with fibrosis. Enrichment of target shRNAs indicates that the knockdown/inhibition of these targets gives a survival advantage to hepatocytes under a chronic liver damaging condition. As enrichment indicates a relative expansion to the control, knockdown or inhibition of the identified genes supports hepatocyte expansion, proliferation and robustness. This is therapeutically beneficial for liver disease interception, accelerating liver regeneration, protecting against liver damage, promoting cell proliferation, stopping and reversing liver fibrosis, and increasing survival.
Targets
The present disclosure relates to inhibition of gene and/or protein expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. Any one or combination of these genes (i.e. any one, two, three, four, five, six, seven, eight or all nine) may be inhibited in the methods provided herein. Any one or combination of these genes may be referred to herein as a target gene(s), target mRNA(s), or target protein(s). One or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be described herein as a “gene or corresponding gene product associated with organ regeneration”.
MFAP4, GRHPR and ITFG1 are found in recurrent amplifications in hepatocellular carcinoma (Nat Med. 2014 October; 20(10): 1138-1146). ABCC4, PAK3, TRNP1, APLN, KIF20A and LTB were all found by the present inventors to be dysregulated in a local patient cohort with non-alcoholic fatty liver disease (NAFLD). Microfibril-associated glycoprotein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen-related domain (FReD) superfamily. Human MFAP4 is identified by UniProtKB P55083.
MFAP4 structure and function is described in e.g. Pilecki B., et al., J. Biol. Chem. 291:1103-1114 (2016), which is hereby incorporated by reference in its entirety.
MFAP4 is an extracellular glycoprotein found in elastic fibres and is required for proper elastic fibre organisation. It specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and it co-localizes with fibrillin-1-positive fibres in vivo. Human MFAP4 has been localized to elastic fibres in a variety of elastic tissues, including aorta, skin, and lung.
MFAP4 is closely associated with remodelling-related diseases, including liver fibrosis, atherosclerosis, arterial injury stimulated remodelling, and asthma (Wang H B et al., J Am Heart Assoc. 2020; 9(17):e015307). Pan Z et al., FASEB J. 2020, 34(11):14250-14263 reported that MFAP4 deficiency alleviates renal fibrosis by inhibiting the activation of NF-KB and TGF-β/Smad signalling pathways and downregulating the expression of fibrosis-related proteins. MFAP4 is produced by activated myofibroblasts and may be a predictive biomarker for severity of hepatic fibrosis (Madsen B S et al., Liver Int. 2020; 40(7): 1701-1712; Seekmose S G, et al., PLoS One. 2015; 10(10):e0140418). Example 2 of the present application shows that genes known to be involved in liver regeneration, e.g. Ptgs2, Areg, Dhrs9, Hmox1 and Nqo1, are upregulated after Mfap4 knockdown.
Alternative splicing of the mRNA transcribed from the human MFAP4 gene yields two isoforms: isoform 1 (UniProtKB: P55083-1, v2; SEQ ID NO: 7156), and isoform 2 (UniProtKB: P55083-2; SEQ ID NO: 7157) in which the amino acid sequence corresponding to positions 1 to 2 of SEQ ID NO: 7156 are replaced with the sequence ‘MGELSPLQRPLATEGTMKAQGVLLKL’.
The 255-amino acid sequence of human MFP4 isoform 1 comprises an N-terminal signal peptide at positions 1-21 of SEQ ID NO: 7156 and the mature protein region at positions 22-255 of SEQ ID NO: 7156. Positions 26-28 of SEQ ID NO: 7156 constitute the cell attachment site and positions 32-255 of SEQ ID NO: 7156 constitute the fibrinogen C-terminal domain.
In this specification, reference to ‘MFAP4’ encompasses: human MFAP4, isoforms of human MFAP4, homologues of human MFAP4 (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, MFAP4 according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7156.
Glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is an NADPH/NADH dependent enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. It reduces toxic intermediate glyoxylate to easily-excreted glycolate and reduces hydroxypyruvate into D-glycerate for use in glucose synthesis. Deficiency of GRHPR is the underlying cause of primary hyperoxaluria type 2 (PH2) and leads to increased urinary oxalate levels, formation of kidney stones and renal failure (Cregeen D P et al., Hum Mol Genet. 1999; 8(11):2063-9). Human GRHPR is identified by UniProtKB Q9UBQ7.
GRHPR structure and function is described in e.g. Rumsby G. and Cregeen D. P. Biochim. Biophys. Acta 1446:383-388 (1999), and Booth et al., J Mol Biol, 2006; 360(1):178-89, which are hereby incorporated by reference in their entirety.
Alternative splicing of the mRNA transcribed from the human GRHPR gene yields two isoforms: isoform 1 (UniProtKB: Q9UBQ7-1, v1; SEQ ID NO: 7158), and isoform 2 (UniProtKB: Q9UBQ7-2; SEQ ID NO: 7159) in which the amino acid sequence corresponding to positions 1 to 21 of SEQ ID NO: 7158 are replaced with the sequence ‘MLGGVPTLCGTGNETWTLLAL’, positions 22-164 of SEQ ID NO: 7158 are missing, and positions 246-328 of SEQ ID NO: 7158 are replaced with the sequence ‘YPRATLPSKPGEEPSPLLPSGDFLPRGLLVRPQAELAGFHKPNNQLRNSWEYTRPPYREEEPSEWAWP VCFSAVAPTRRGLAHSSVASGSVPREPLQAHYPPPQRAGLEDLKGPLEAASHTAEPGFVWLWFSDTLNL MLLGGQTLKLTWS’.
The 328-amino acid sequence of human GRHPR isoform 1 comprises NADP binding sites at positions 217, 243, 162-164, 185-188 and 295 of SEQ ID NO: 7158, and substrate (glyoxylate/hydroxypyruvate) binding sites at positions 83-84, 245, 269, and 293-296 of SEQ ID NO: 7158.
In this specification, reference to ‘GRHPR’ encompasses: human GRHPR, isoforms of human GRHPR, homologues of human GRHPR (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, GRHPR according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7158.
T-cell immunomodulatory protein (ITFG1; also known as Protein TIP, Integrin-alpha FG-GAP repeat-containing protein 1, or Linkin/LNKN-1) is a modulator of T cell function. Human ITFG1 is identified by UniProtKB Q8TB96.
ITFG1 structure and function is described in e.g. Fiscella M., et al., Nat. Biotechnol. 21:302-307 (2003), which is hereby incorporated by reference in its entirety. Treatment of primary human and murine T cells with ITFG1 in vitro resulted in the secretion of IFN-gamma, TNF-alpha, and IL-10, whereas in vivo ITFG1 reportedly has a protective effect in a mouse acute graft-versus-host disease (GVHD) model. The interaction between ITFG1 and the ATPase RUVBL1 is reported to be required for breast cancer cell invasion and progression (Fan W. et al., Biochim Biophys Acta Gen Subj. 2017; 1861(7):1788-1800).
The 612-amino acid sequence of human ITFG1 is shown in SEQ ID NO: 7160 (UniprotKB: Q8TB96-1, v1). This sequence comprises: an N-terminal signal peptide at positions 1-33 of SEQ ID NO: 7160, an FG-GAP repeat at positions 258-293 of SEQ ID NO: 7160, and a transmembrane domain at positions 567-587 of SEQ ID NO: 7160.
In this specification, reference to ‘ITFG1’ encompasses: human ITFG1, isoforms of human ITFG1, homologues of human ITFG1 (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, ITFG1 according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7160.
ATP-binding cassette sub-family C member 4 (ABCC4; also known as multidrug resistance protein 4 (MRP4)) is an ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. It transports a range of endogenous molecules that have a key role in cellular communication and signalling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins. It is expressed in several tissues, including hepatocytes, with highest expression in the kidney and choroid plexus (Maher J M, et al., Drug Metab. Dispos., 33 (2005), pp. 947-955). Human ABCC4 is identified by UniProtKB 015439.
ABCC4 structure and function is described in e.g. Russel et al., Trends Pharmacol Sci. 2008, 29(4):200-7, which is hereby incorporated by reference in its entirety. ABCC4 is an inducible gene in the liver following toxic acetaminophen exposure in both humans and rodents. In mice, ABCC4 deficiency is linked to increased risk of liver injury, altered gut epithelial function and altered drug disposition, although protein expression is reportedly increased in human livers with steatosis, alcoholic cirrhosis, and diabetic cirrhosis (More V R et al., Drug Metab Dispos. 2013; 41(5): 1148-1155).
Alternative splicing of the mRNA transcribed from the human ABCC4 gene yields four isoforms: isoform 1 (UniProtKB: 015439-1, v3; SEQ ID NO: 7161), isoform 2 (015439-2, SEQ ID NO: 7162) in which the amino acid sequence corresponding to positions 679-725 of SEQ ID NO: 7161 are missing, isoform 3 (015439-3, SEQ ID NO: 7163) in which the amino acid sequence corresponding to positions 846-859 of SEQ ID NO: 7161 are replaced with the sequence ‘RWDLAVLSWLVSNS’ and positions 860-1325 of SEQ ID NO: 7161 are missing, and isoform 4 (015439-4, SEQ ID NO: 7164) in which the amino acid sequence corresponding to positions 103-177 of SEQ ID NO: 7161 are missing, the amino acid sequence corresponding to positions 846-859 of SEQ ID NO: 7161 are replaced with the sequence ‘RWDLAVLSWLVSNS’, and the amino acid sequence corresponding to positions 860-1325 of SEQ ID NO: 7161 are missing.
The 1325-amino acid sequence of human ABCC4 isoform 1 comprises: an ABC transmembrane type-1 1 domain at positions 92-377, an ABC transporter 1 domain at positions 410-633, an ABC transmembrane type-1 2 domain at positions 714-1005, an ABC transporter 2 domain at positions 1041-1274, and ATP binding regions at positions 445-452 and 1075-1082 of SEQ ID NO: 7161.
In this specification, reference to ‘ABCC4’ encompasses: human ABCC4, isoforms of human ABCC4, homologues of human ABCC4 (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, ABCC4 according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7161.
p21-activated kinase 3 (PAK3; also known as Serine/threonine-protein kinase PAK 3, Beta-PAK or Oligophrenin-3) is a serine/threonine protein kinase that plays a role in a variety of different signalling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. It phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. PAK3 is also a core mediator of integrin beta-1 signalling (a critical mediator of HSC activation and progression of fibrotic disease). Human PAK3 is identified by UniProtKB 075914.
PAK3 structure and function is described in e.g. Deleris P., et al., J. Biol. Chem. 286:6470-6478 (2011) and Chong C. et al., J. Biol. Chem. 276:17347-17353 (2001), which are both hereby incorporated by reference in their entirety.
Alternative splicing of the mRNA transcribed from the human PAK3 gene yields four isoforms: isoform 1 (UniProtKB: 075914-1, v2; SEQ ID NO: 7165), isoform 2 (075914-2, SEQ ID NO: 7166) in which the amino acid sequence corresponding to positions 93-107 of SEQ ID NO: 7165 are missing, isoform 3 (075914-3, SEQ ID NO: 7167) in which the amino acid at position 92 of SEQ ID NO: 7165 is replaced with the sequence ‘TNSPFQTSRPVTVASSQSEGKM’, and isoform 4 (075914-4, SEQ ID NO: 7168) in which the amino acid sequence corresponding to positions 92-107 of SEQ ID NO: 7165 are replaced with the sequence ‘TNSPFQTSRPVTVASSQSEGKM’.
The 559-amino acid sequence of human PAK3 isoform 1 comprises: a CRIB domain at positions 70-83 and a protein kinase domain at positions 283-534 of SEQ ID NO: 7165.
In this specification, reference to ‘PAK3’ encompasses: human PAK3, isoforms of human PAK3, homologues of human PAK3 (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, PAK3 according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7165.
TMF-regulated nuclear protein 1 (TRNP1) is a DNA-binding factor that regulates the expression of a subset of genes and plays a key role in tangential, radial, and lateral expansion of the brain neocortex. Human TRNP1 is identified by UniProtKB Q6NT89.
TRNP1 structure and function is described in e.g. Stahl R. et al., Cell 153:535-549 (2013), which is hereby incorporated by reference in its entirety.
The 227-amino acid sequence of human TRNP1 is shown in SEQ ID NO: 7169 (UniprotKB: Q6NT89-1, v2).
In this specification, reference to ‘TRNP1’ encompasses: human TRNP1, isoforms of human TRNP1, homologues of human TRNP1 (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, TRNP1 according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7169.
Apelin (APLN) is a peptide ligand for the G-protein coupled apelin receptor (APLNR). The APLN system plays important and various roles in the physiology and pathophysiology of many organs, including regulation of blood pressure, cardiac contractility, angiogenesis, metabolic balance, and cell proliferation, apoptosis or inflammation. Apelin is expressed in the heart, endothelium, vascular smooth muscle cells (VSMCs), brain, kidney, testis, ovary, liver and adipose tissue, with the highest expression levels in the lung and the mammary gland. Human APLN is identified by UniProtKB Q9ULZ1.
APLN structure and function is described in e.g. Tatemoto K. et al., Biochem. Biophys. Res. Commun. 251:471-476 (1998), and Lee D. K. et al., J. Neurochem. 74:34-41 (2000), which are both hereby incorporated by reference in their entirety.
The 77-amino acid sequence of human APLN is shown in SEQ ID NO: 7170 (UniprotKB: Q9ULZ1-1, v1). SEQ ID NO: 7170 encompasses a signal peptide at positions 1-22 and a propeptide at positions 23-41. SEQ ID NO: 7170 is cleaved into one or more active peptides by proteolytic processing: Apelin-36 (SEQ ID NO: 7171) at positions 42-77 of SEQ ID NO: 7170, Apelin-31 (SEQ ID NO: 7172) at positions 47-77 of SEQ ID NO: 7170, Apelin-28 (SEQ ID NO: 7173) at positions 50-77 of SEQ ID NO: 7170, or Apelin-13 (SEQ ID NO: 7174) at positions 65-77 of SEQ ID NO: 7170.
In this specification, reference to ‘APLN’ encompasses: human APLN, isoforms of human APLN, homologues of human APLN (i.e. encoded by the genome of a non-human animal), proteolytic peptides derived from human APLN, and variants thereof. In some embodiments, APLN according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7170.
Kinesin-like protein KIF20A (also known as GG10_2, Mitotic kinesin-like protein 2 (MKIp2), Rab6-interacting kinesin-like protein (RAB6KIFL), Rabkinesin-6) is a mitotic kinesin required for chromosome passenger complex (CPC)-mediated cytokinesis. KIF20A is a target for polo-like kinase 1 (PIk1), and phosphorylated KIF20A binds to the polo box domain of PIk1. Phosphorylation of KIF20A by PIk1 is necessary for the spatial restriction of PIk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis. Human KIF20A is identified by UniProtKB 095235.
KIF20A structure and function is described in e.g. Neef R. et al., J Cell Biol. 2003; 162(5): 863-75, which is hereby incorporated by reference in its entirety.
Alternative splicing of the mRNA transcribed from the human KIF20A gene yields two isoforms: isoform 1 (UniProtKB: 095235-1, v1; SEQ ID NO: 7175), and isoform 2 (UniProtKB: 095235-2; SEQ ID NO: 7176) in which the amino acid sequence corresponding to positions 65-82 of SEQ ID NO: 7175 are missing.
The 890-amino acid sequence of human KIF20A isoform 1 comprises: a kinesin motor domain at positions 64-507 and a coiled coil domain at positions 611-762 of SEQ ID NO: 7175.
In this specification, reference to ‘KIF20A’ encompasses: human KIF20A, isoforms of human KIF20A, homologues of human KIF20A (i.e. encoded by the genome of a non-human animal), and variants thereof.
In some embodiments, KIF20A according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7175.
Lymphotoxin-beta (LTB, also known as Tumor necrosis factor C (TNF-C), Tumor necrosis factor ligand superfamily member 3) is a pro-inflammatory cytokine belonging to the TNF family that binds to receptors LTBR/TNFRSF3. It participates in the regulation of immune and inflammatory responses and, along with other LT-related cytokines such as LT-alpha, TNFα and LIGHT (TNFSF14) and their receptors, plays a role in the development and homeostasis of secondary lymphoid organs. Human LTB is identified by UniProtKB Q06643.
LTB structure and function is described in e.g. Sudhamsu J., et al., Proc Natl Acad Sci USA 110:19896-19901 (2013); Browning J. L., et al., Cell 72:847-856 (1993), Neville M. J. & Campbell R. D. J. Immunol. 162:4745-4754 (1999); Crowe P. D. et al., Science. 1994; 264(5159):707-10; and Bjordahl R. L. et al., Curr Opin Immunol. 2013, 25(2): 222-229, which are all hereby incorporated by reference in their entirety.
Alternative splicing of the mRNA transcribed from the human LTB gene yields two isoforms: isoform 1 (UniProtKB: Q06643-1, v1; SEQ ID NO: 7177), and isoform 2 (UniProtKB: Q06643-2; SEQ ID NO: 7178) in which the amino acid sequence corresponding to positions 53-77 of SEQ ID NO: 7177 are replaced with the sequence ‘GLGFRSCQRRSQKQISAPGSQLPTS’ and positions 78-244 of SEQ ID NO: 7177 are missing.
The 244-amino acid sequence of human LTB isoform 1 comprises: a cytoplasmic domain at positions 1-18, a transmembrane domain at positions 19-48, and an extracellular domain at positions 49-244 of SEQ ID NO: 7177.
In this specification, reference to ‘LTB’ encompasses: human LTB, isoforms of human LTB, homologues of human LTB (i.e. encoded by the genome of a non-human animal), and variants thereof. In some embodiments, LTB according to the present disclosure comprises or consists of an amino acid sequence having at 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 7177.
As used herein, a “fragment”, “variant” or “homologue” of a protein may optionally be characterised as having at least 60%, preferably one of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of the reference protein (e.g. a reference isoform). In some embodiments, fragments, variants, isoforms and homologues of a reference protein may be characterised by ability to perform a function performed by the reference protein.
A “fragment” generally refers to a fraction of the reference protein. A “variant” generally refers to a protein having an amino acid sequence comprising one or more amino acid substitutions, insertions, deletions or other modifications relative to the amino acid sequence of the reference protein, but retaining a considerable degree of sequence identity (e.g. at least 60%) to the amino acid sequence of the reference protein. An “isoform” generally refers to a variant of the reference protein expressed by the same species as the species of the reference protein. A “homologue” generally refers to a variant of the reference protein produced by a different species as compared to the species of the reference protein. Homologues include orthologues.
A “fragment” may be of any length (by number of amino acids), although may optionally be at least 20% of the length of the reference protein (that is, the protein from which the fragment is derived) and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.
In some embodiments, the target gene/protein (i.e. MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB) is a target gene/protein from a mammal (any species in the class Mammalia, e.g. a primate (rhesus, cynomolgous, non-human primate or human) and/or a rodent (e.g. rat or mouse).
Isoforms, fragments, variants or homologues of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB isoform from a given species, e.g. human.
A homologue of a human gene described herein may be from any animal. In some embodiments, a homologue of a human gene described herein may be from a mammal. In some embodiments, the mammal may be a non-human mammal, e.g. a primate (e.g. a non-human primate, e.g. an animal of the genus Macaca (e.g. Macaca fascicularis, Macaca mulatta), e.g. a non-human hominid (e.g. Pan troglodytes)). In some embodiments, the mammal may be a rabbit, guinea pig, rat, mouse or animal of the order Rodentia, cat, dog, pig, sheep, goat, an animal of the order Bos (e.g. cattle), an animal of the family Equidae (e.g. horse) or donkey.
Homologues of a human protein described herein may optionally be characterised as having 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NOs: 7156 to 7178. Variants of a human protein described herein may optionally be characterised as having 70% or greater amino acid sequence identity, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to the amino acid sequence of SEQ ID NOs: 7156 to 7178.
Isoforms, fragments, variants or homologues may optionally be functional isoforms, fragments, variants or homologues, e.g. having a functional property/activity of the reference MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, as determined by analysis by a suitable assay for the functional property/activity.
Inhibition of Targets
The present invention is concerned with inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (i.e. a target gene/protein described herein). That is, the invention is concerned with inhibition of the expression and/or activity of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and the downstream functional consequences thereof.
Inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB encompasses decreased/reduced expression (gene and/or protein expression) of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, and/or decreased/reduced activity of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, relative to the level of expression/activity observed in the absence of inhibition. “Inhibition” may herein also be referred to as “antagonism”. Any one, two, three, four, five, six, seven, eight or nine of the genes/proteins may be inhibited in the methods according to the present disclosure.
In some embodiments, inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be characterised by one or more of the following (relative to the uninhibited state):

- Reduce expression (e.g. gene and/or protein expression) of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce the level of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce/prevent transcription of nucleic acid encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Increase degradation of RNA (e.g. mRNA) encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce the level of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein;
- Reduce/prevent post-transcriptional processing (e.g. splicing, translation, post-translational processing) of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Promote/increase degradation of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein;
- Reduce/prevent the level of a MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB function; and/or
- Reduce/prevent interaction between MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and an interaction partner for MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.

Gene expression can be determined by means well known to the skilled person. The level of RNA encoding one or more of the target proteins can be determined e.g. by techniques such as RT-qPCR, northern blot, etc. By way of illustration, qRT-PCR may be used to determine the level of RNA encoding a target protein.
A reduction in the level of RNA encoding a target protein may e.g. be the result of reduced transcription of nucleic acid encoding the target protein, or increased degradation of RNA encoding the target protein.
Reduced transcription of nucleic acid encoding a target protein may be a consequence of inhibition of assembly and/or activity of factors required for transcription of the DNA encoding the target protein. Increased degradation of RNA encoding a target protein may be a consequence of increased enzymatic degradation of RNA encoding the target protein, e.g. as a consequence of RNA interference (RNAi), and/or reduced stability of RNA encoding the target protein.
Protein expression can be determined by means well known to the skilled person. The level of protein encoding a target protein can be determined e.g. by antibody-based methods including western blot, immunohisto/cytochemistry, flow cytometry, ELISA, ELISPOT, or by reporter-based methods.
A reduction in the level of a target protein may e.g. be the result of reduced level of RNA encoding the target protein, reduced post-transcriptional processing of RNA encoding the target protein, or increased degradation of the target protein.
Reduced post-transcriptional processing of a target protein may be e.g. reduced splicing of pre-mRNA encoding the target protein to mature mRNA encoding the target protein, reduced translation of mRNA encoding the target protein, or reduced post-translational processing of the target protein.
Reduced splicing of pre-mRNA encoding the target protein to mature mRNA encoding the target protein may be a consequence of inhibition of assembly and/or activity of factors required for splicing. Reduced translation of mRNA encoding the target protein may be a consequence of inhibition of assembly and/or activity of factors required for translation. Reduced post-translational processing (e.g. enzymatic processing, folding) of the target protein may be a consequence of inhibition of assembly and/or activity of factors required for post-translational processing of the target protein. Increased degradation of the target protein may be a consequence of increased enzymatic (e.g. protease-mediated) degradation of the target protein.
In some embodiments, inhibition of a target gene/protein may be characterised by a reduced level of a function of the target protein. A function of the target protein may be any functional property of the target protein.
An interaction partner may be any nucleic acid or protein which interacts with, or jointly contributes to a shared function with, any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments, an interaction partner for MFAP4 is integrin αvβ3, tropoelastin, fibrillin-1, fibrillin-2, desmosine, LOX, MFAP2, FBLN1, FBLN2, MFAP5, EFEMP2, EFEMP1, SFTPD, or elastin.
In some embodiments, an interaction partner for GRHPR is glyoxylate, hydroxypyruvate, D-glycerate, AGXT, HYI, GLYCTK, PGP, GLO1, HAO1, HAO2, DAO, NADPH or NADH.
In some embodiments, an interaction partner for ITFG1 is RUVBL1, RUVBL2, alpha-tubulin, TIPIN, ATP9A, ASCC2, RFX7, or TM7SF3.
In some embodiments, an interaction partner for ABCC4 is ATP, ABCG4, SNX27, ABCA3, ABCE1, MRPS7, SLC22A8, SLCO1B1, NR1H4 or SLC22A6.
In some embodiments, an interaction partner for PAK3 is PAK1, CDC42, NCK1, MAPK14, RAC1, PXN, GIT1, GIT2, ARHGEF7 or ARHGEF6.
In some embodiments, an interaction partner for TRNP1 is TMF1, FAM18A, CNIH3, SMARCC2, FAM19A3, TBC1D3A, TBC1D3D, ARHGAP11B, or GPR56.
In some embodiments, an interaction partner for APLN is APLNR, AGTR1, AGT, CXCR4, CCR5, KNG1, NPY, PDYN, NMU, or POMC.
In some embodiments, an interaction partner for KIF20A is MAD2L1, AURKB, RACGAP1, KIF11, PLK1, CDCA8, KIF4A, CENPE, PRC1, or INCENP.
In some embodiments, an interaction partner for LTB is LTBR, LTA, TNF, TNFSF14, TNFRSF1B, TNFSF13B, TNFRSF11A, CD40LG, MAP3K14, TNFSF11.
Functional properties of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB can be analysed using appropriate assays, e.g. in vitro assays.
In some embodiments, MFAP4 inhibition increases expression and/or activation of one or more of Ptgs2, Areg, Dhrs9, Hmox1, Nqo1, P70S6k, p38, mTOR, and/or ERK2. In some embodiments, an inhibitor of MFAP4 activates mTOR, p70S6K, ERK and p38 signalling pathways.
Inhibition of interaction between a target protein and an interaction partner for the target protein can be identified e.g. by detection of a reduction in the level of interaction between the target protein and the interaction partner, relative to a control, uninhibited condition. The ability of proteins to interact can be analysed by methods well known to the skilled person, such as co-immunoprecipitation, and resonance energy transfer (RET) assays.
Inhibition of target protein function can also be evaluated by analysis of one or more correlates of target protein function. That is, target protein function can be evaluated by analysis of downstream functional consequences of target protein function. For example, inhibition of target protein function can be identified by detection of reduced expression (gene and/or protein expression) and/or activity of one or more proteins whose expression is directly/indirectly upregulated as a consequence of target protein function. Inhibition of target protein function can also be identified by detection of increased expression (gene and/or protein expression) and/or activity of one or more proteins whose expression is directly/indirectly downregulated as a consequence of target protein function.
Inhibitors
Provided herein are inhibitors that target one or more genes/proteins from the group selected from: MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and LTB.
An “inhibitor of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB” refers to any agent capable of inhibiting any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB expression and/or function. Such agents may be effectors of (i.e. may directly or indirectly cause) inhibition of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB as described hereinabove.
Agents capable of inhibiting any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be referred to herein as MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB inhibitors. MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB inhibitors may also be referred to herein as antagonists of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, or MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB antagonists.
“An inhibitor” of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may refer to any agent capable of inhibiting any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB. In addition, “An inhibitor of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB” may refer to two or more agents capable of inhibiting two, three, four, five, six, seven, eight, or nine target genes/proteins selected from the group consisting of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and LTB. Multiple inhibitors may be used in the methods of the present disclosure to target two or more of the target genes/proteins.
In some embodiments, an inhibitor of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (i.e. a target protein) may:

- Reduce/prevent expression (e.g. gene and/or protein expression) of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce the level of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce/prevent transcription of nucleic acid encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Increase degradation of RNA (e.g. mRNA) encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reduce the level of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein;
- Reduce/prevent post-transcriptional processing (e.g. splicing, translation, post-translational processing) of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Promote/increase degradation of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein;
- Reduce/prevent the level of a MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB function; and/or
- Reduce/prevent interaction between MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and an interaction partner for MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.

It will be appreciated that a given inhibitor may display more than one of the properties recited in the preceding paragraph. A given inhibitor may be evaluated for the properties recited in the preceding paragraph using suitable assays. The assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. The assays may be e.g. in vivo assays, i.e. performed in non-human animals.
Where assays are cell-based assays, they may comprise treating cells with an inhibitor (e.g. a nucleic acid) in order to determine whether the inhibitor displays one or more of the recited properties. Assays may employ species labelled with detectable entities in order to facilitate their detection. Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities/concentrations of a given inhibitor (e.g. a dilution series). It will be appreciated that the cells are preferably cells that express the target protein to be inhibited, e.g. liver cells (e.g. HepG2 cells or HuH7 cells).
Analysis of the results of such assays may comprise determining the concentration at which 50% of the maximal level of the relevant activity is attained. The concentration of nucleic acid at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the inhibitor in relation to the relevant activity, which may also be referred to as the ‘EC₅₀’. By way of illustration, the EC₅₀of a given inhibitor (e.g. inhibitory nucleic acid) for increasing degradation of RNA encoding a target protein may be the concentration at which 50% of the maximal level of degradation of RNA encoding a target protein is achieved.
Depending on the property, the EC₅₀may also be referred to as the ‘half-maximal inhibitory concentration’ or ‘IC₅₀’, this being the concentration of inhibitor at which 50% of the maximal level of inhibition of a given property is observed. By way of illustration, the IC₅₀of a given inhibitor (e.g. inhibitory nucleic acid) for reducing expression of a gene encoding a target protein may be the concentration at which 50% of the maximal level of inhibition of expression of the gene is achieved.
Agents capable of reducing/preventing gene expression of any one or more MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. reducing the level of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB; reducing/preventing transcription of nucleic acid encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB; and/or increasing degradation of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB) may be identified using assays comprising detecting the level of RNA encoding the target protein, e.g. by RT-qPCR (a technique well known to the skilled person). The methods may employ primers and/or probes for the detection and/or quantification of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Such assays may comprise introducing (e.g. by transfection) into cells that express the target protein in in vitro culture (i) a putative inhibitor (e.g. an inhibitory nucleic acid), or (ii) a control agent (e.g. a control nucleic acid, such as a nucleic acid known not to influence the level of RNA encoding the target protein), and subsequently (e.g. after an appropriate period of time, i.e. a period of time sufficient for a reduction in the level of gene expression of the target protein/transcription of nucleic acid encoding the target protein/level of RNA encoding the target protein or an increase in the level of degradation of RNA encoding the target protein to be observed) measuring the level of RNA encoding the target protein in cells according to (i) and (ii), and (iii) comparing the level of RNA encoding the target protein detected to determine whether the putative inhibitor reduces/prevents gene expression of the target protein, reduces/prevents transcription of nucleic acid encoding the target protein, reduces the level of RNA encoding the target protein, and/or increases degradation of RNA encoding the target protein.
Agents capable of reducing protein expression of any one or more MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. reducing the level of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein, increasing degradation of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein) may be identified using assays comprising detecting the level of the target protein, e.g. using antibody/reporter-based methods (western blot, ELISA, immunohisto/cytochemistry, etc.). Such assays may comprise treating cells/tissue with the agent, and subsequently comparing the level of the target protein in such cells/tissue to the level of the target protein in cells/tissue of an appropriate control condition (e.g. untreated/vehicle-treated cells/tissue).
The methods may employ antibodies specific for the target protein. Such assays may comprise introducing (e.g. by transfection) into cells that express a target protein in in vitro culture (i) a putative inhibitor (e.g. an inhibitory nucleic acid), or (ii) a control agent (e.g. a nucleic acid known not to influence the level of the target protein), and subsequently (e.g. after an appropriate period of time, i.e. a period of time sufficient for a reduction in the level of the target protein to be observed) measuring the level of the target protein in cells according to (i) and (ii), and (iii) comparing the level of the target protein detected to determine whether the putative inhibitor reduces the level of the target protein and/or reduces/prevents translation of mRNA encoding the target protein.
Agents capable of reducing the level of a function of any one or more MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. a function of a target protein as described herein) may be identified using assays comprising detecting the level of the relevant function. Such assays may comprise introducing (e.g. by transfection) into cells that express the target protein in in vitro culture (i) a putative inhibitor (e.g. an inhibitory nucleic acid), or (ii) a control agent (e.g. a nucleic acid known not to influence target protein function), and subsequently (e.g. after an appropriate period of time, i.e. a period of time sufficient for a reduction in the level of a function of the target protein to be observed) measuring the level of a function of the target protein in cells according to (i) and (ii), and (iii) comparing the level of the function of the target protein detected to determine whether the putative inhibitor reduces the level of a function of the target protein.
Reference herein to ‘a function of the target protein’ may refer to any functional property of, and/or activity mediated by, MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein. Agents capable of reducing/preventing normal splicing of pre-mRNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be identified using assays comprising detecting and/or quantifying the level of RNA (e.g. mature mRNA) encoding one or more isoforms of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. Such assays may comprise quantifying RNA (e.g. mature mRNA) encoding one or more isoforms of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB by RT-qPCR. The methods may employ primers and/or probes for the detection and/or quantification of mature mRNA produced by canonical splicing of pre-mRNA transcribed from a gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, and/or primers and/or probes for the detection and/or quantification of mature mRNA produced by alternative splicing of pre-mRNA transcribed from a gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Mature mRNA produced by canonical splicing of pre-mRNA transcribed from a gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be mature mRNA encoding the major isoform produced by expression of the gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. The major isoform may be the most commonly produced/detected isoform. For example, mature mRNA produced by canonical splicing of pre-mRNA transcribed from human MFAP4 may be mature mRNA encoding human MFAP4 isoform 1 (i.e. having the amino acid sequence shown in SEQ ID NO: 7156). Mature mRNA produced by alternative splicing of pre-mRNA transcribed from a gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be mature mRNA encoding an isoform other than the major isoform produced by expression of said gene. For example, mature mRNA produced by alternative splicing of pre-mRNA transcribed from human MFAP4 may be mature mRNA encoding an isoform of human MFAP4 other than isoform 1 (i.e. having an amino acid sequence non-identical to SEQ ID NO: 7156); e.g. mature mRNA encoding human MFAP4 isoform 2 (i.e. having an amino acid sequence shown in SEQ ID NO: 7157).
Such assays may comprise introducing (e.g. by transfection) into cells that express MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in in vitro culture (i) a putative inhibitor (e.g. an inhibitory nucleic acid), or (ii) a control agent (e.g. a nucleic acid known not to influence splicing of pre-mRNA encoding the target gene), and subsequently (e.g. after an appropriate period of time, i.e. a period of time sufficient for an effect on splicing of pre-mRNA encoding the target gene to be observed) measuring the level of mature mRNA encoding one or more isoforms of the target gene in cells according to (i) and (ii), and (iii) comparing the level of mature mRNA encoding the isoform(s) to determine whether the putative inhibitor reduces/prevents normal splicing of pre-mRNA encoding the target gene.
Agents capable of reducing interaction between a target protein described herein and an interaction partner for said target protein may be identified using assays comprising detecting the level of interaction between the target protein and its interaction partner, e.g. using antibody/reporter-based methods. The level of interaction between the target protein and its interaction partner can be analysed e.g. using resonance energy transfer techniques (e.g. FRET, BRET), or methods analysing a correlate of interaction between the target protein and its interaction partner. Assays may comprise treating cells/tissue with the agent, and subsequently comparing the level of interaction between the target protein and its interaction partner in such cells/tissue to the level of interaction between the target protein and its interaction partner in cells/tissue of an appropriate control condition (e.g. untreated/vehicle-treated cells/tissue). The level of interaction between the target protein and its interaction partner can also be analysed e.g. using techniques such as ELISA, surface plasmon resonance or biolayer interferometry analysis. Assays may comprise comparing the level of interaction between the target protein and its interaction partner in the presence of the agent to the level of interaction between the target protein and its interaction partner in an appropriate control condition (e.g. the absence of the agent).
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing expression of a gene encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level of expression observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to inhibit expression of the relevant gene, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing expression of a gene encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level of expression observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to inhibit expression of the relevant gene, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of RNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of RNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of RNA encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of transcription of nucleic acid encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce transcription of nucleic acid encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of transcription of nucleic acid encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce transcription of nucleic acid encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of a function of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of the function of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of a function of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of the function of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of binding of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to an interaction partner to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of binding, in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of binding of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to an interaction partner to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce the level of the relevant binding, in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing normal splicing of pre-mRNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce normal splicing of pre-mRNA encoding the relevant target protein(s), in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing the level of normal splicing of pre-mRNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce normal splicing of pre-mRNA encoding the relevant target protein(s), in a given assay.
In some embodiments, an inhibitor according to the present disclosure may be capable of reducing translation of mRNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 1 times, e.g. one of ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce translation of mRNA encoding the relevant target protein(s), in a given assay. In some embodiments, an inhibitor according to the present disclosure may be capable of reducing translation of mRNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to less than 100%, e.g. one of ≤99%, ≤95%, ≤90%, ≤85%, ≤80%, ≤75%, ≤70%, ≤65%, ≤60%, ≤55%, ≤50%, ≤45%, ≤40%, ≤35%, ≤30%, ≤25%, ≤20%, ≤15%, ≤10%, ≤5%, or ≤1% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to reduce translation of mRNA encoding the relevant target protein(s), in a given assay.
Preferred levels of reduction in accordance with the preceding eight paragraphs are reduction to less than 0.5 times/≤50%, e.g. one of less than 0.4 times/≤40%, less than 0.3 times/≤30%, less than 0.2 times/≤20%, less than 0.15 times/≤15%, or less than 0.1 times/≤10%.
In some embodiments, an inhibitor according to the present disclosure may be capable of increasing degradation of RNA encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to more than 1 times, e.g. one of ≥1.01 times, ≥1.02 times, ≥1.03 times, ≥1.04 times, ≥1.05 times, ≥1.1 times, ≥1.2 times, ≥1.3 times, ≥1.4 times, ≥1.5 times, ≥1.6 times, ≥1.7 times, ≥1.8 times, ≥1.9 times, ≥2 times, ≥3 times, ≥4 times, ≥5 times, ≥6 times, ≥7 times, ≥8 times, ≥9 times or ≥10 times the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to increase degradation of RNA encoding the relevant target protein(s), in a given assay. In some embodiments, an inhibitor according to the present disclosure prevents or silences expression of a gene encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. In some embodiments, an inhibitor according to the present disclosure prevents or silences expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB at the protein level. As used herein, expression of a given gene/protein may be considered to be ‘prevented’ or ‘silenced’ where the level of expression is reduced to less than 0.1 times/≤10% of the level observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to be an inhibitor of expression of the relevant gene(s)/protein(s).
In preferred embodiments, an inhibitor (e.g. an inhibitory nucleic acid, such as an siRNA or shRNA) according to the present disclosure inhibits greater than 50%, e.g. one of ≥60%, ≥61%, ≥62%, ≥63%, ≥64%, ≥65%, ≥66%, ≥67%, ≥68%, ≥69%, ≥70%, ≥71%, ≥72%, ≥73%, ≥74%, ≥75%, ≥76%, ≥77%, ≥78%, ≥79%, ≥80%, ≥81%, ≥82%, ≥83%, ≥84%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% of the gene and/or protein expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to inhibit gene and/or protein expression of the relevant gene(s)/protein(s), in a given assay.
In preferred embodiments, an inhibitor (e.g. an inhibitory nucleic acid, such as an siRNA or shRNA) according to the present disclosure inhibits greater than 50%, e.g. one of ≥60%, ≥61%, ≥62%, ≥63%, ≥64%, 65%, ≥66%, ≥67%, ≥68%, ≥69%, ≥70%, ≥71%, ≥72%, ≥73%, ≥74%, ≥75%, ≥76%, ≥77%, ≥78%, ≥79%, 80%, ≥81%, ≥82%, ≥83%, ≥84%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% of the gene expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. as determined by qRT-PCR) observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to inhibit gene and/or protein expression of the relevant gene(s)/protein(s), in a given assay.
In preferred embodiments, an inhibitor (e.g. an inhibitory nucleic acid, such as an siRNA or shRNA) according to the present disclosure inhibits greater than 50%, e.g. one of ≥60%, ≥61%, ≥62%, ≥63%, ≥64%, ≥65%, ≥66%, ≥67%, ≥68%, ≥69%, ≥70%, ≥71%, ≥72%, ≥73%, ≥74%, ≥75%, ≥76%, ≥77%, ≥78%, ≥79%, ≥80%, ≥81%, ≥82%, ≥83%, ≥84%, ≥85%, ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% of the protein expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. as determined by ELISA) observed in the absence of the inhibitor, or in the presence of the same quantity of a control agent known not to inhibit gene and/or protein expression of the relevant gene(s)/protein(s), in a given assay.
In some embodiments, an inhibitor (e.g. an inhibitory nucleic acid, such as an siRNA or shRNA) according to the present disclosure may inhibit gene and/or protein expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB with an IC₅₀of ≤1 μM, e.g. one of ≤500 nM, ≤100 nM, ≤75 nM, ≤50 nM, ≤40 nM, ≤30 nM, ≤20 nM, ≤15 nM, ≤12.5 nM, ≤10 nM, ≤9 nM, ≤8 nM, ≤7 nM, ≤6 nM, ≤5 nM, ≤4 nM ≤3 nM, ≤2 nM, ≤1 nM, ≤900 pM, ≤800 pM, ≤700 pM, ≤600 pM, ≤500 pM, ≤400 pM, ≤300 pM, ≤200 pM, ≤100 pM, ≤50 pM, ≤40 pM, ≤30 pM, ≤20 pM, ≤10 pM or ≤1 pM.
In some embodiments an inhibitor according to the present disclosure may inhibit gene expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. as determined by qRT-PCR) with an IC₅₀of ≤1 nM, ≤900 pM, ≤800 pM, ≤700 pM, ≤600 pM, ≤500 pM, ≤400 pM, ≤300 pM, ≤200 pM, ≤100 pM, ≤50 pM, ≤40 pM, ≤30 pM, ≤20 pM, ≤10 pM or ≤1 pM.
In some embodiments an inhibitor according to the present disclosure may inhibit protein expression of any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. as determined by ELISA) with an IC₅₀of ≤1 nM, ≤900 pM, ≤800 pM, ≤700 pM, ≤600 pM, ≤500 pM, ≤400 pM, ≤300 pM, ≤200 pM, ≤100 pM, ≤50 pM, ≤40 pM, ≤30 pM, ≤20 pM, ≤10 pM or ≤1 pM.
Types of Inhibitors
Inhibitors according to the present disclosure may be any kind of agent possessing the appropriate inhibitory activity.
The term “inhibitor” as used herein refers to an agent that decreases or inhibits at least one function or biological activity of a target molecule, such as those described herein.
An inhibitor according to the present disclosure may be a molecule that is capable of binding to any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB mRNA or protein, a molecule that is capable of binding to an interacting partner of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, or a molecule capable of reducing expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments an inhibitor is capable of binding to a polypeptide according to any one or more of SEQ ID NO: 7156 to 7178, or a mRNA according to any one of SEQ ID NO: 7179 to 7195.
In some embodiments an inhibitor targets, e.g. is capable of binding to, a functional domain or region of any one or more of SEQ ID NO: 7156 to 7178. In some embodiments an inhibitor targets a region comprising positions 22-255, 26-28 or 32-255 of SEQ ID NO: 7156. In some embodiments an inhibitor targets a region comprising one or more of positions 83-84, 162-164, 185-188, 217, 243, 245, 269, and 293-296 of SEQ ID NO: 7158. In some embodiments an inhibitor targets a region comprising positions 258-293 of SEQ ID NO: 7160. In some embodiments an inhibitor targets a region comprising positions 92-377, 410-633, 714-1005, 1041-1274, 445-452, or 1075-1082 of SEQ ID NO: 7161. In some embodiments an inhibitor targets a region comprising positions 70-83 or 283-534 of SEQ ID NO: 7165. In some embodiments an inhibitor targets a region comprising positions 64-507 or 611-762 of SEQ ID NO: 7175. In some embodiments an inhibitor targets a region comprising positions 1-18, 19-48, or 49-244 of SEQ ID NO: 7177.
In some embodiments an inhibitor is capable of binding to an interacting partner of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, such as those described hereinabove.
Such binding molecules can be identified using any suitable assay for detecting binding of a molecule to the relevant factor (i.e. a target gene/protein described herein, or an interaction partner for said protein(s)). Such assays may comprise detecting the formation of a complex between the relevant factor and the molecule.
In some embodiments, the inhibitor is a nucleic acid, peptide, antibody, antigen-binding molecule or small molecule inhibitor.
Small molecule inhibitors that bind to the target mRNA/proteins described herein, or their binding partners, can be identified by screening of small molecule libraries. As used herein, a “small molecule” refers to a low molecular weight (<1000 daltons, typically between ˜300-700 daltons) organic compound. Small molecule inhibitors that bind to the target mRNA/proteins described herein can be identified e.g. using a method described in Horswill A R et al., PNAS, 2004,101 (44) 15591-15596, which is hereby incorporated by reference in its entirety.
An inhibitor of GRHPR may be 4-hydroxy-2-oxoglutarate.
An inhibitor of ABCC4 may be Methotrexate, Mercaptopurine, Zidovudine, Dipyridamole, Probenecid, Sulfinpyrazone, Fluorouraci, Rucaparib, Adefovir dipivoxil, Cefazolin, Tyrphostin AG1478, Dantrolene, Glafenine, Nalidixic Acid or Prazosin.
An inhibitor of PAK3 may be FRAX597.
An inhibitor of APLN may be ML221, an apelin receptor (APJ) antagonist.
An inhibitor of KIF20A may be BKS0349 or Paprotrain.
Inhibitors provided herein include peptides/polypeptides, e.g. peptide aptamers, thioredoxins, monobodies, anticalin, Kunitz domains, avimers, knottins, fynomers, atrimers, DARPins, affibodies, nanobodies (i.e. single-domain antibodies (sdAbs)) affilins, armadillo repeat proteins (ArmRPs), OBodies and fibronectin—reviewed e.g. in Reverdatto et al., Curr Top Med Chem. 2015; 15(12): 1082-1101, which is hereby incorporated by reference in its entirety (see also e.g. Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48). Inhibitors include peptides/polypeptides that can be identified by screening of libraries of the relevant peptides/polypeptides. The peptide/polypeptide inhibitors may be referred to as inhibitory peptides/polypeptides.
Inhibitory peptides/polypeptides may also include e.g. peptide/polypeptide interaction partners for the target gene/mRNA/protein of interest (i.e. MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB).
Peptide/polypeptide interaction partners may be based on an interaction partner for the target gene/mRNA/protein of interest, and may e.g. comprise a fragment of an interaction partner said target(s). Peptide/polypeptide interaction partners may be based on one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, and may e.g. comprise a fragment of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB that binds to an interaction partner for said mRNA/protein. Such agents may behave as ‘decoy’ molecules, and preferably display competitive inhibition of interaction between MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and a corresponding interaction partner for MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
An inhibitor of MFAP4 may, for example, be a peptide/polypeptide that is capable of blocking the interaction between MFAP4 and an integrin receptor, integrin αvβ3, tropoelastin, fibrillin-1, fibrillin-2, desmosine, LOX, MFAP2, FBLN1, FBLN2, MFAP5, EFEMP2, EFEMP1, SFTPD, or elastin.
An inhibitor of GRHPR may, for example, be a peptide/polypeptide that is capable of blocking the interaction between GRHPR and glyoxylate, hydroxypyruvate, D-glycerate, AGXT, HYI, GLYCTK, PGP, GLO1, HAO1, HAO2, DAO, NADPH or NADH.
An inhibitor of ITFG1 may, for example, be a peptide/polypeptide that is capable of blocking the interaction between ITFG1 and RUVBL1, RUVBL2, alpha-tubulin, TIPIN, ATP9A, ASCC2, RFX7, or TM7SF3.
An inhibitor of ABCC4 may, for example, be a peptide/polypeptide that is capable of blocking the interaction between ABCC4 and ATP, ABCG4, SNX27, ABCA3, ABCE1, MRPS7, SLC22A8, SLCO1B1, NR1H4 or SLC22A6.
An inhibitor of PAK3 may, for example, be a peptide/polypeptide that is capable of blocking the interaction between PAK3 and PAK1, CDC42, NCK1, MAPK14, RAC1, PXN, GIT1, GIT2, ARHGEF7 or ARHGEF6.
An inhibitor of TRNP1 may, for example, be a peptide/polypeptide that is capable of blocking the interaction between TRNP1 and TMF1, FAM18A, CNIH3, SMARCC2, FAM19A3, TBC1D3A, TBC1D3D, ARHGAP11B, or GPR56.
An inhibitor of APLN may, for example, be a peptide/polypeptide that is capable of blocking the interaction between APLN and APLNR, AGTR1, AGT, CXCR4, CCR5, KNG1, NPY, PDYN, NMU, or POMC.
An inhibitor of KIF20A may, for example, be a peptide/polypeptide that is capable of blocking the interaction between KIF20A and MAD2L1, AURKB, RACGAP1, KIF11, PLK1, CDCA8, KIF4A, CENPE, PRC1, or INCENP.
An inhibitor of LTB may, for example, be a peptide/polypeptide that is capable of blocking the interaction between LTB and LTBR, LTA, TNF, TNFSF14, TNFRSF1B, TNFSF13B, TNFRSF11A, CD40LG, MAP3K14, TNFSF11.
In some embodiments, an inhibitory peptide/polypeptide may comprise or consist of an amino acid sequence having at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of an interaction partner for one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, or the amino acid sequence of a fragment thereof.
In some embodiments, an inhibitory peptide/polypeptide may comprise or consist of an amino acid sequence having at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, or the amino acid sequence of a fragment thereof. In such embodiments it will be appreciated that the inhibitory peptide/polypeptide will lack normal activity and/or have reduced activity compared to the wildtype version of the protein. For example, in some embodiments an inhibitory peptide/polypeptide may be a variant (e.g. mutant) version of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB having reduced function relative to wildtype MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Inhibitory peptides/polypeptides include aptamers. Nucleic acid aptamers are reviewed e.g. in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202, and may be identified and/or produced by the method of Systematic Evolution of Ligands by EXponential enrichment (SELEX), or by developing SOMAmers (slow off-rate modified aptamers) (Gold L et al. (2010) PLoS ONE 5(12):e15004). Aptamers and SELEX are described in Tuerk and Gold, Science (1990) 249(4968):505-10, and in WO 91/19813. Nucleic acid aptamers may comprise DNA and/or RNA, and may be single stranded or double stranded. They may comprise chemically modified nucleic acids, for example in which the sugar and/or phosphate and/or base is chemically modified. Such modifications may improve the stability of the aptamer or make the aptamer more resistant to degradation and may include modification at the 2′ position of ribose. Nucleic acid aptamers may be chemically synthesised, e.g. on a solid support. Solid phase synthesis may use phosphoramidite chemistry. Briefly, a solid supported nucleotide is detritylated, then coupled with a suitably activated nucleoside phosphoramidite to form a phosphite triester linkage. Capping may then occur, followed by oxidation of the phosphite triester with an oxidant, typically iodine. The cycle may then be repeated to assemble the aptamer (e.g., see Sinha, N. D.; Biernat, J.; McManus, J.; Köster, H. Nucleic Acids Res. 1984, 12, 4539; and Beaucage, S. L.; Lyer, R. P. (1992). Tetrahedron 48 (12): 2223). Peptide aptamers and methods for their generation and identification are reviewed in Reverdatto et al., Curr Top Med Chem. (2015) 15(12):1082-101, which is hereby incorporated by reference in its entirety.
Inhibitory peptides/polypeptides also include antibodies (immunoglobulins) such as monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and fragments and derivatives thereof (e.g. Fv, scFv, Fab, scFab, F(ab′)₂, Fab₂, diabodies, triabodies, scFv-Fc, minibodies, single domain antibodies (e.g. VhH), etc.).
In some embodiments, an inhibitor described herein is an antibody that is capable of binding to one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
An inhibitor of MFAP4 may be an antibody with catalog number PA5-42013 (ThermoFisher) or ab169757 (abcam). An inhibitor of GRHPR may be an antibody with catalog number PA5-54652 (ThermoFisher) or ab155604 (abcam). An inhibitor of ITFG1 may be an antibody with catalog number PA5-54067 (ThermoFisher) or TA339563 (ORIGENE). An inhibitor of ABCC4 may be an antibody with catalog number PA5-82019 (ThermoFisher) or ab15602 (abcam). An inhibitor of PAK3 may be an antibody with catalog number PA5-79781 (ThermoFisher) or ab40808 (abcam). An inhibitor of TRNP1 may be an antibody with catalog number PA5-71277 (ThermoFisher) or ab174303 (abcam). An inhibitor of APLN may be an APLN-blocking antibody. An inhibitor of APLN may be an antibody with catalog number PA5-114860 (ThermoFisher) or ab125213 (abcam). An inhibitor of KIF20A may be an antibody with catalog number PA5-38648 (ThermoFisher). An inhibitor of LTB may be an antibody (e.g. a recombinant Mouse Anti-LTA and LTB Antibody (CBL543)).
Inhibitors/inhibitory molecules that bind to any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, or that bind to an interacting partner thereof, may display specific binding to the relevant factor (i.e. the relevant mRNA/protein, or the interaction partner for said mRNA/protein). As used herein, “specific binding” refers to binding which is selective, and which can be discriminated from non-specific binding to non-target molecules.
An inhibitor or binding molecule that specifically binds to any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB preferably binds to any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB with greater affinity, and/or with greater duration than it binds to other, non-target molecules. Such binding molecules may be described as being “specific for” any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. An inhibitor or binding molecule that specifically binds to an interaction partner for any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB preferably binds to the interaction partner for any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB with greater affinity, and/or with greater duration than it binds to other, non-target molecules; such binding molecules may be described as being “specific for” the interaction partner for any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments an inhibitor/binding molecule described herein inhibits the ability of any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to bind to a corresponding interaction partner (i.e. an interaction partner for MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB, respectively). In some embodiments the inhibitor/binding molecule behaves as a competitive inhibitor of interaction between any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and a corresponding interaction partner. The binding molecule may occupy, or otherwise reduce access to, a region of the protein required for binding to a corresponding interaction partner, or may occupy, or otherwise reduce access to, a region of an interaction partner required for binding to the corresponding protein.
The ability of an inhibitor, e.g. a binding molecule, to inhibit interaction between a protein of interest and a corresponding interaction partner can be evaluated e.g. by analysis of interaction in the presence of, or following incubation of one or both of the interaction partners with, the inhibitor. An example of a suitable assay to determine whether a given binding agent is capable of inhibiting interaction between a protein of interest and a corresponding interaction partner is a competition ELISA.
An inhibitor described herein may be a molecule capable of reducing expression of any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. A “molecule capable of reducing expression of any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB” refers to a molecule which is capable of reducing gene, mRNA and/or protein expression of any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. In some embodiments the molecule reduces or prevents the expression of a polypeptide according to SEQ ID NO: 7156 to 7178. In some embodiments the molecule reduces or prevents the expression of a polypeptide from a sequence according to SEQ ID NO: 7179 to 7195.
Repression of expression of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB or an isoform thereof will preferably result in a decrease in the quantity of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB expressed by a cell/tissue/organ/organ system/subject. For example, in a given cell the repression of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB by administration of a suitable nucleic acid will result in a decrease in the level of expression relative to an untreated cell. Repression may be partial. Preferred degrees of repression are at least 50%, more preferably one of at least 60%, 70%, 80%, 85% or 90%. A level of repression between 90% and 100% is considered a ‘silencing’ of expression or function. Gene and protein expression may be determined as described herein or by methods in the art that are well known to a skilled person.
In some embodiments, inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may comprise modification of a cell(s) to reduce or prevent expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying nucleic acid encoding one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. The modification causes the cell to have a reduced level of gene and/or protein expression of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB as compared to an unmodified cell.
In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may comprise modifying a gene encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises introducing an insertion, substitution or deletion into a nucleic acid sequence encoding MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises introducing a modification which reduces or prevents the expression of a polypeptide according to any one of SEQ ID NO: 7156 to 7178 from the modified nucleic acid sequence. In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying a cell to comprise an allele of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB which does not encode an amino acid sequence according to any one of SEQ ID NO: 7156 to 7178. In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying a cell to lack nucleic acid encoding a polypeptide according to any one of SEQ ID NO: 7156 to 7178.
In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying the relevant gene(s) to introduce a premature stop codon in the sequence transcribed from said gene(s). In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying the relevant gene(s) to encode a truncated and/or non-functional polypeptide(s). In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB comprises modifying the relevant gene(s) to encode polypeptide(s) which is/are misfolded and/or degraded.
Methods for modifying nucleic acids encoding proteins of interest and agents for achieving the same are well known in the art, and include e.g. including modification of the target nucleic acid by homologous recombination, and target nucleic acid editing using site-specific nucleases (SSNs).
Suitable methods may employ targeting by homologous recombination, which is reviewed, for example, in Mortensen Curr Protoc Neurosci. (2007) Chapter 4:Unit 4.29 and Vasquez et al., PNAS 2001, 98(15): 8403-8410, both of which are hereby incorporated by reference in their entirety. Targeting by homologous recombination involves the exchange of nucleic acid sequence through crossover events guided by homologous sequences.
In some embodiments the methods employ target nucleic acid editing using SSNs. Gene editing using SSNs is reviewed e.g. in Eid and Mahfouz, Exp Mol Med. 2016 October; 48(10): e265, which is hereby incorporated by reference in its entirety. Enzymes capable of creating site-specific double strand breaks (DSBs) can be engineered to introduce DSBs to target nucleic acid sequence(s) of interest. DSBs may be repaired by either error-prone non-homologous end-joining (NHEJ), in which the two ends of the break are rejoined, often with insertion or deletion of nucleotides. Alternatively DSBs may be repaired by highly homology-directed repair (HDR), in which a DNA template with ends homologous to the break site is supplied and introduced at the site of the DSB.
SSNs capable of being engineered to generate target nucleic acid sequence-specific DSBs include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) systems.
ZFN systems are reviewed e.g. in Umov et al., Nat Rev Genet. (2010) 11(9):636-46, which is hereby incorporated by reference in its entirety. ZFNs comprise a programmable Zinc Finger DNA-binding domain and a DNA-cleaving domain (e.g. a FokI endonuclease domain). The DNA-binding domain may be identified by screening a Zinc Finger array capable of binding to the target nucleic acid sequence.
TALEN systems are reviewed e.g. in Mahfouz et al., Plant Biotechnol J. (2014) 12(8):1006-14, which is hereby incorporated by reference in its entirety. TALENs comprise a programmable DNA-binding TALE domain and a DNA-cleaving domain (e.g. a FokI endonuclease domain). TALEs comprise repeat domains consisting of repeats of 33-39 amino acids, which are identical except for two residues at positions 12 and 13 of each repeat which are repeat variable di-residues (RVDs). Each RVD determines binding of the repeat to a nucleotide in the target DNA sequence according to the following relationship: ‘HD’ binds to C, ‘NI’ binds to A, ‘NG’ binds to T and ‘NN’ or ‘NK’ binds to G (Moscou and Bogdanove, Science (2009) 326(5959):1501.).
CRISPR/Cas9 and related systems e.g. CRISPR/Cpf1, CRISPR/C2c1, CRISPR/C2c2 and CRISPR/C2c3 are reviewed e.g. in Nakade et al., Bioengineered (2017) 8(3):265-273, which is hereby incorporated by reference in its entirety. These systems comprise an endonuclease (e.g. Cas9, Cpf1 etc.) and the single-guide RNA (sgRNA) molecule. The sgRNA can be engineered to target endonuclease activity to nucleic acid sequences of interest.
In some embodiments, inhibition of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB employs a site-specific nuclease (SSN) system targeting the relevant nucleic acid sequence(s). Accordingly in some embodiments the inhibitor comprises or consists of an SSN system targeting nucleic acid(s) encoding one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. In some embodiments inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB employs nucleic acid(s) encoding a SSN system targeting the relevant nucleic acid sequence(s).
In some embodiments, the SSN system targets a region of the nucleic acid encoding a domain of a MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein required for protein function, e.g. a domain as described herein.
In some embodiments the SSN system is a ZFN system, a TALEN system, CRISPR/Cas9 system, a CRISPR/Cpf1 system, a CRISPR/C2c1 system, a CRISPR/C2c2 system or a CRISPR/C2c3 system.
In some embodiments the SSN system is a CRISPR/Cas9 system. In such embodiments, the inhibition may employ nucleic acid(s) encoding a CRISPR RNA (crRNA) targeting nucleic acid encoding one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, and a trans-activating crRNA (tracrRNA) for processing the crRNA to its mature form.
Nucleic Acid Inhibitors
In some embodiments, the inhibitor is a nucleic acid inhibitor. A nucleic acid inhibitor may also be described herein as an inhibitory nucleic acid.
Nucleic acid inhibitors according to the present disclosure may comprise or consist of DNA and/or RNA. Nucleic acid inhibitors may be single-stranded (e.g. in the case of antisense oligonucleotides (e.g. gapmers)). Nucleic acid inhibitors may be double-stranded or may comprise double-stranded region(s) (e.g. in the case of siRNA, shRNA, etc.). Inhibitory nucleic acids may comprise both double-stranded and single-stranded regions (e.g. in the case of shRNA and pre-miRNA molecules, which are double-stranded in the stem region of the hairpin structure, and single-stranded in the loop region of the hairpin structure).
In some embodiments, a nucleic acid inhibitor according to the present disclosure may be an antisense nucleic acid as described herein. In some embodiments, a nucleic acid inhibitor may comprise an antisense nucleic acid as described herein. In some embodiments, a nucleic acid inhibitor may encode an antisense nucleic acid as described herein.
As used herein, an ‘antisense nucleic acid’ refers to a nucleic acid (e.g. DNA or RNA) that is complementary to at least a portion of a target nucleotide sequence (e.g. of RNA encoding a target gene described herein). Antisense nucleic acids according to the present disclosure are preferably single-stranded nucleic acids, and bind via complementary Watson-Crick base-pairing to a target nucleotide sequence. Complementary base-pairing may involve hydrogen bonding between complementary base pairs. Antisense nucleic acids may be provided as single-stranded molecules, as for example in the case of antisense oligonucleotides, or may be comprised in double-stranded molecular species, as for example in the case of siRNA, shRNA and pre-miRNA molecules.
Complementary base-pairing between the antisense nucleic acid and its target nucleotide sequence may be complete. In such embodiments the antisense nucleic acid comprises, or consists of, the reverse complement of its target nucleotide sequence, and complementary base-pairing occurs between each nucleotide of the target nucleotide sequence and complementary nucleotides in the antisense nucleic acid. Alternatively, complementary base-pairing between the antisense nucleic acid and its target nucleotide sequence may be incomplete/partial. In such embodiments complementary base-pairing occurs between some, but not all, nucleotides of the target nucleotide sequence and complementary nucleotides in the antisense nucleic acid.
Such binding between nucleic acids through complementary base pairing may be referred to as ‘hybridisation’. Through binding to its target nucleotide sequence, an antisense nucleic acid may form a nucleic acid complex comprising (i) the antisense nucleic acid and (ii) a target nucleic acid comprising the target nucleotide sequence.
The nucleotide sequence of an antisense nucleic acid is sufficiently complementary to its target nucleotide sequence such that it binds or hybridises to the target nucleotide sequence. It will be appreciated that an antisense nucleic acid preferably has a high degree of sequence identity to the reverse complement of its target nucleotide sequence. In some embodiments, the antisense nucleic acid comprises or consists of a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to the reverse complement of its target nucleotide sequence.
In some embodiments, an antisense nucleic acid according to the present disclosure comprises: a nucleotide sequence which is the reverse complement of its target nucleotide sequence, or a nucleotide sequence comprising 1 to 10 (e.g. one of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) substitutions relative to the reverse complement of its target nucleotide sequence.
In some embodiments, the target nucleotide sequence for an antisense nucleic acid according to the present disclosure comprises, or consists of, 5 to 100 nucleotides, e.g. one of 10 to 80, 12 to 50, or 15 to 30 nucleotides (e.g. 20 to 27, e.g. ˜21 to 23). In some embodiments, the target nucleotide sequence for an antisense nucleic acid according to the present disclosure comprises or consists of DNA and/or RNA. In some embodiments, the target nucleotide sequence for an antisense nucleic acid according to the present disclosure comprises or consists of RNA.
In some embodiments, the antisense nucleic acid reduces/prevents transcription of nucleic acid comprising its target nucleotide sequence. In some embodiments, the antisense nucleic acid reduces/prevents association of factors required for normal transcription (e.g. enhancers, RNA polymerase) with nucleic acid comprising its target nucleotide sequence.
In some embodiments, the antisense nucleic acid increases/potentiates degradation of nucleic acid comprising its target nucleotide sequence, e.g. through RNA interference. In some embodiments, the antisense nucleic acid reduces/prevents translation of nucleic acid comprising its target nucleotide sequence, e.g. through RNA interference or antisense degradation via RNase H.
RNA interference is described e.g. in Agrawal et al., Microbiol. Mol. Bio. Rev. (2003) 67(4): 657-685 and Hu et al., Sig. Transduc. Tar. Ther. (2020) 5(101), both of which are hereby incorporated by reference in their entirety. Briefly, double-stranded RNA molecules are recognised by the argonaute component of the RNA-induced silencing complex (RISC). The double-stranded RNAs are separated into single strands and integrated into an active RISC, by the RISC-Loading Complex (RLC). The RISC-integrated strands bind to their target RNA through complementary base pairing, and depending on the identity of the RISC-integrated RNA and degree of complementarity to the target RNA, the RISC then either cleaves the target RNA resulting in its degradation, or otherwise blocks access of ribosomes thereby preventing its translation. RNAi based therapeutics have been approved for a number of indications (Kim, Chonnam Med J. (2020) 56(2): 87-93).
In some embodiments, the antisense nucleic acid reduces/prevents normal post-transcriptional processing (e.g. splicing and/or translation) of nucleic acid comprising its target nucleotide sequence. In some embodiments, the antisense nucleic acid reduces or alters splicing of pre-mRNA comprising its target nucleotide sequence to mature mRNA. In some embodiments, the antisense nucleic acid reduces translation of mRNA comprising its target nucleotide sequence to protein.
In some embodiments, the antisense nucleic acid reduces/prevents association of factors required for normal post-transcriptional processing (e.g. components of the spliceosome) with nucleic acid comprising its target nucleotide sequence. In such instances, the antisense nucleic may be referred to as a ‘splice-switching’ nucleic acid.
Splice-switching nucleic acids are reviewed e.g. in Haves and Hastings, Nucleic Acids Res. (2016) 44(14): 6549-6563, which is hereby incorporated by reference in its entirety. Splice-switching nucleic acids include e.g. splice-switching oligonucleotides (SSOs). They disrupt the normal splicing of target RNA transcripts by blocking the RNA:RNA base-pairing and/or protein:RNA binding interactions that occur between components of the splicing machinery and pre-mRNA. Splice-switching nucleic acids may be employed to alter the number/proportion of mature mRNA transcripts encoding a protein described herein. Splice-switching nucleic acids may be designed to target a specific region of the target transcript, e.g. to effect skipping of exon(s) of interest, e.g. exons encoding domains/regions of interest. SSOs often comprise alterations to oligonucleotide sugar-phosphate backbones in order to reduce/prevent RNAse H degradation, such as e.g. phosphorothioate linkages, phosphorodiamidate linkages such as phosphorodiamidate morpholino (PMOs), and may comprise e.g. peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methoxyethyl nucleotide modifications, e.g. 2′O-methyl (2′OMe) and 2′-O-methoxyethyl (MOE) ribose modifications and/or 5′-methylcytosine modifications.
In some embodiments, the antisense nucleic acid inhibits/reduces translation of nucleic acid comprising its target nucleotide sequence. In some embodiments, the antisense nucleic acid reduces/prevents association of factors required for translation (e.g. ribosomes) with nucleic acid comprising its target nucleotide sequence.
As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a gene (e.g. a gene associated with organ regeneration), including mRNA that is a product of RNA processing of a primary transcription product.
It will be appreciated that the target nucleotide sequence to which an antisense nucleic acid binds is a nucleotide sequence encoding a protein which it is desired to inhibit expression of. Accordingly, in aspects and embodiments of the present disclosure, the target nucleotide sequence for an antisense nucleic acid is a nucleotide sequence of a gene encoding any one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of RNA encoded by a gene encoding any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB. In some embodiments, the target nucleotide sequence is a nucleotide sequence of RNA encoding any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB. In some embodiments, the target nucleotide sequence comprises one or more nucleotides of an exon of RNA encoding any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB. In some embodiments, the target nucleotide sequence is a nucleotide sequence of an exon of RNA encoding any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB.
In some embodiments, the target nucleotide sequence is a nucleotide sequence provided in Table 14.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001198695.2 (GI: 1677501926, version 2), which is the NCBI Reference Sequence for human MFAP4 transcript variant 1 mRNA (SEQ ID NO: 7179), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_002404.3 (GI: 1677501522, version 3), which is the NCBI Reference Sequence for human MFAP4 transcript variant 2 mRNA (SEQ ID NO: 7180), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_012203.2 (GI: 1519473711, version 2) which is the NCBI Reference Sequence for human GRHPR transcript variant 1 mRNA (SEQ ID NO: 7181), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_030790.5 (GI: 1653961895, version 5) which is the NCBI Reference Sequence for human ITFG1 transcript variant 1 mRNA (SEQ ID NO: 7182), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_005845.5 (GI: 1813751621, version 5) which is the NCBI Reference Sequence for human ABCC4 transcript variant 1 mRNA (SEQ ID NO: 7183), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001105515.3 (GI: 1677498821, version 3) which is the NCBI Reference Sequence for human ABCC4 transcript variant 2 mRNA (SEQ ID NO: 7184), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001301829.2 (GI: 1677530022, version 2) which is the NCBI Reference Sequence for human ABCC4 transcript variant 3 mRNA (SEQ ID NO: 7185), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001301830.2 (GI: 1677498275, version 2) which is the NCBI Reference Sequence for human ABCC4 transcript variant 4 mRNA (SEQ ID NO: 7186), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001128166.3 (GI: 1889680926, version 3) which is the NCBI Reference Sequence for human PAK3 transcript variant 1 mRNA (SEQ ID NO: 7187), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_002578.5 (GI: 1519316149, version 5) which is the NCBI Reference Sequence for human PAK3 transcript variant 2 mRNA (SEQ ID NO: 7188), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001128167.3 (GI: 1890283404, version 3) which is the NCBI Reference Sequence for human PAK3 transcript variant 3 mRNA (SEQ ID NO: 7189), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001128168.3 (GI: 1676441496, version 3) which is the NCBI Reference Sequence for human PAK3 transcript variant 4 mRNA (SEQ ID NO: 7190), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_001013642.3 (GI: 1519242294, version 3) which is the NCBI Reference Sequence for human TRNP1 mRNA (SEQ ID NO: 7191), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_017413.5 (GI: 1519315208, version 5) which is the NCBI Reference Sequence for human APLN mRNA (SEQ ID NO: 7192), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_005733.3 (GI: 1519313609, version 3) which is the NCBI Reference Sequence for human KIF20A transcript variant 1 mRNA (SEQ ID NO: 7193), or a portion thereof.
In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_002341.2 (GI: 1720810086, version 2) which is the NCBI Reference Sequence for human LTB transcript variant 1 mRNA (SEQ ID NO: 7194), or a portion thereof. In some embodiments, the target nucleotide sequence is a nucleotide sequence of NM_009588.1 (GI: 6996015, version 1) which is the NCBI Reference Sequence for human LTB transcript variant 2 mRNA (SEQ ID NO: 7195), or a portion thereof.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to the reverse complement of any one of SEQ ID NOs: 7179 to 7195, or a portion thereof, e.g. calculated over the length of the antisense nucleic acid or over the length of the portion of the reference sequence.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one of SEQ ID NOs: 7179 to 7195, or a portion thereof, e.g. calculated over the length of the antisense nucleic acid or over the length of the portion of the reference sequence.
In some embodiments the antisense nucleic acid and/or the portion of the reference sequence is 5 to 50, 5 to 40, 8 to 30, 8 to 25, 10 to 25, 15 to 25, or 19 to 22 nucleotides in length. Antisense nucleic acids described herein may comprise thymine or uracil residues. Where antisense nucleic acids described herein are defined by reference to sequence identity with a reference sequence, the nucleic acids may comprise uracil residues in place of any thymine residues in the reference sequence, or vice versa.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to a sequence, or to the reverse complement of a sequence, in any one or more of Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and/or 13, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence from a Table.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 1 to 7155, or to the reverse complement of any one or more of SEQ ID NOs: 1 to 7155, e.g. calculated over the length of the antisense nucleic acid or the length of the reference sequence.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 14 to 7114 or 7141 to 7155, or to the reverse complement of any one or more of SEQ ID NOs: 14 to 7114 or 7141 to 7155, e.g. calculated over the length of the antisense nucleic acid or the length of the reference sequence.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one of SEQ ID NOs: 1 to 13, or to the reverse complement of any one of SEQ ID NOs: 1 to 13, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one of SEQ ID NOs: 7115 to 7140, or to the reverse complement of any one of SEQ ID NOs: 7115 to 7140, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 14 to 347, and/or to the reverse complement of any one or more of SEQ ID NOs: 14 to 347, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of MFAP4, e.g. human MFAP4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NOs: 1, 2, 15, 19 or 25, and/or to the reverse complement of SEQ ID NOs: 1, 2, 15, 19, or 25, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of MFAP4, e.g. human MFAP4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NOs: 7092, 7093, 7141, 7142, 7146, 7147, 7151, 7152 and/or 7097 to 7102, and/or to the reverse complement of SEQ ID NOs: 7092, 7093, 7141, 7142, 7146, 7147, 7151, 7152 and/or 7097 to 7102, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of MFAP4, e.g. human MFAP4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NOs: 7097 or 7100, and/or to the reverse complement of SEQ ID NOs: 7097 or 7100, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of MFAP4, e.g. human MFAP4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 7115 to 7120, and/or to the reverse complement of any one or more of SEQ ID NOs: 7115 to 7120, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of MFAP4, e.g. mouse MFAP4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 348 to 456, and/or to the reverse complement of any one or more of SEQ ID NOs: 348 to 456, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of GRHPR, e.g. human GRHPR.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 3, 4, 5, 349, 350 and/or 351, and/or to the reverse complement of any one or more of SEQ ID NOs: 3, 4, 5, 349, 350, and/or 351, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of GRHPR, e.g. human GRHPR.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 7094, 7143, 7148, 7153 and/or 7103 to 7108, and/or to the reverse complement of any one or more of SEQ ID NOs: 7094, 7143, 7148, 7153 and/or 7103 to 7108, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of GRHPR, e.g. human GRHPR.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 7121 to 7129, and/or to the reverse complement of any one or more of SEQ ID NOs: 7121 to 7129, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of GRHPR, e.g. mouse GRHPR.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 457 to 1482, and/or to the reverse complement of any one or more of SEQ ID NOs: 457 to 1482, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ITFG1, e.g. human ITFG1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 6, 7, 457, 465, 468, 470, and/or 473, and/or to the reverse complement of any one or more of SEQ ID NOs: 6, 7, 457, 465, 468, 470, and/or 473, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ITFG1, e.g. human ITFG1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 7095, 7096, 7144, 7145, 7149, 7150, 7154, 7155, and/or 7109 to 7114, and/or to the reverse complement of any one or more of SEQ ID NOs: 7095, 7096, 7144, 7145, 7149, 7150, 7154, 7155, and/or 7109 to 7114, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ITFG1, e.g. human ITFG1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 7130 to 7140, and/or to the reverse complement of any one or more of SEQ ID NOs: 7130 to 7140, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ITFG1, e.g. mouse ITFG1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 1483 to 2208, and/or to the reverse complement of any one or more of SEQ ID NOs: 1483 to 2208, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ABCC4, e.g. human ABCC4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 1483, 1485, 1486, 1488, 1489 and/or 1490, and/or to the reverse complement of any one or more of SEQ ID NOs: 1483, 1485, 1486, 1488, 1489 and/or 1490, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of ABCC4, e.g. human ABCC4.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 2209 to 5060, and/or to the reverse complement of any one or more of SEQ ID NOs: 2209 to 5060, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of PAK3, e.g. human PAK3.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 2209, 2225 and/or 2234, and/or to the reverse complement of any one or more of SEQ ID NOs: 2209, 2225 and/or 2234 e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of PAK3, e.g. human PAK3.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5061 to 5389, and/or to the reverse complement of any one or more of SEQ ID NOs: 5061 to 5389, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of TRNP1, e.g. human TRNP1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5061 and/or 5062, and/or to the reverse complement of any one or more of SEQ ID NOs: 5061 and/or 5062 e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of TRNP1, e.g. human TRNP1.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5390 to 5966, and/or to the reverse complement of any one or more of SEQ ID NOs: 5390 to 5966, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of APLN, e.g. human APLN.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5390, 5391, 5392 and/or 5393, and/or to the reverse complement of any one or more of SEQ ID NOs: 5390, 5391, 5392 and/or 5393, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of APLN, e.g. human APLN.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5967 to 6974, and/or to the reverse complement of any one or more of SEQ ID NOs: 5967 to 6974, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of KIF20A, e.g. human KIF20A.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 5967, 5970 and/or 5971, and/or to the reverse complement of any one or more of SEQ ID NOs: 5967, 5970 and/or 5971, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of KIF20A, e.g. human KIF20A.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 6975 to 7091, and/or to the reverse complement of any one or more of SEQ ID NOs: 6975 to 7091, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of LTB, e.g. human LTB.
In some embodiments, the antisense nucleic acid comprises or consists of a sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to any one or more of SEQ ID NOs: 6977, 6978 and/or 6993, and/or to the reverse complement of any one or more of SEQ ID NOs: 6977, 6978 and/or 6993, e.g. calculated over the length of the antisense nucleic acid or over the length of the reference sequence. The antisense nucleic acid may be capable of reducing gene and/or protein expression of LTB, e.g. human LTB.
The antisense nucleic acid may comprise or consist of a sequence that hybridises to a sequence listed in any of Tables 1 to 14, or a sequence that hybridises to the complement of a sequence listed in any of Tables 1 to 14.
In some embodiments, a nucleic acid inhibitor is an antisense oligonucleotide (ASO). ASOs are single-stranded nucleic acid molecules comprising or consisting of an antisense nucleic acid to a target nucleotide sequence. An antisense oligonucleotide according to the present disclosure may comprise or consist of an antisense nucleic acid as described herein.
ASOs can modify expression of RNA molecules comprising their target nucleotide sequence by altering splicing, or by recruiting RNase H to degrade RNA comprising the target nucleotide sequence. RNase H recognises nucleic acid complex molecules formed when the ASO binds to RNA comprising its target nucleotide sequence. ASOs according to the present disclosure may comprise or consist of an antisense nucleic acid according to the present disclosure. ASOs may comprise 10 to 40 (e.g. 17 to 30, 20 to 27, 21 to 23) nucleotides in length. Many ASOs are designed as chimeras, comprising a mix of bases with different chemistries, or as gapmers, comprising a central DNA portion surrounded by ‘wings’ of modified nucleotides. ASOs are described in e.g. Scoles et al., Neurol Genet. 2019 April; 5(2): e323. ASOs sometimes comprise alterations to the sugar-phosphate backbone in order to increase their stability and/or reduce/prevent RNAse H degradation, such as e.g. phosphorothioate linkages, phosphorodiamidate linkages such as phosphorodiamidate morpholino (PMOs), and may comprise e.g. peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methoxyethyl nucleotide modifications, e.g. 2′O-methyl (2′OMe) and 2′-O-methoxyethyl (MOE) ribose modifications and/or 5′-methylcytosine modifications.
In some embodiments, a nucleic acid inhibitor is selected from: an siRNA, dsiRNA, miRNA, shRNA, pri-miRNA, pre-miRNA, saRNA, snoRNA, or antisense oligonucleotide (e.g. a gapmer), or a nucleic acid encoding the same. In some embodiments, a nucleic acid inhibitor is selected from: an siRNA, dsiRNA, miRNA, shRNA. In some embodiments, a nucleic acid inhibitor is an siRNA. In some embodiments, a nucleic acid inhibitor is an shRNA.
The nucleic acid inhibitor may be an RNAi agent (e.g. siRNA, shRNA or miRNA-based shRNA or gRNA for CRISR/CAS9 knockout) or a nucleic acid encoding an RNAi agent that reduces expression of a gene/mRNA, e.g. one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some embodiments, an inhibitory nucleic acid may comprise an antisense nucleic acid described herein, e.g. as part of a larger nucleic acid species. For example, in some embodiments, an inhibitory nucleic acid may be an siRNA, dsiRNA, miRNA, shRNA, pri-miRNA, pre-miRNA, saRNA or snoRNA comprising an antisense nucleic acid described herein.
In some embodiments, an inhibitory nucleic acid is a small interfering RNA (siRNA). As used herein, ‘siRNA’ refers to a double-stranded RNA molecule having a length between 17 to 30 (e.g. 20 to 27, e.g. ˜21 to 23) base pairs, which is capable of engaging the RNA interference (RNAi) pathway for the targeted degradation of target RNA. Double-stranded siRNA molecules may be formed as a nucleic acid complex of RNA strands having a high degree of complementarity. The strand of the double-stranded siRNA molecule having complementarity to a target nucleotide sequence (i.e. the antisense nucleic acid) may be referred to as the ‘guide’ strand, and the other strand may be referred to as the ‘passenger’ strand. The structure and function of siRNAs is described e.g. in Kim and Rossi, Biotechniques. 2008 April; 44(5): 613-616.
The RNAi agent may contain one or more overhang regions and/or capping groups at the 3′-end, 5′-end, or both ends of one or both strands e.g. comprising one or two or three nucleotides (e.g. a ‘UU’ 3′ overhang, a ‘TT’ 3′ overhang, or a ‘CCA’ 5′ overhang). The overhang can be 1-6 nucleotides in length, for instance 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. The first and second strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers.
In some embodiments, a passenger strand of an siRNA according to the present disclosure may comprise a ‘CCA’ modification at the 5′ end, i.e. the addition of nucleotides ‘CCA’. In some embodiments, a passenger strand of an siRNA according to the present disclosure may comprise a ‘TT’ modification at the 3′ end, e.g. replacing the 3′ two nucleotides.
In some embodiments, the guide strand of an siRNA according to the present disclosure may comprise or consist of an antisense nucleic acid according to an embodiment of an antisense nucleic acid described herein.
In some embodiments an siRNA according to the present disclosure (e.g. in Tables 1-11) may be contained within a longer shRNA sequence (e.g. in Tables 12 and 13) that undergoes processing to form the siRNA.
The term “RNAi agent” or “RNAi” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. RNAi agent directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). The RNAi agent modulates, e.g., inhibits, the expression of a gene associated with organ regeneration in a cell, e.g., a cell within a subject, such as a mammalian subject. The term “RNAi agent” includes both shRNAs (e.g. in Table 12 or 13), or precursor RNAs that are processed by RISC into siRNAs (e.g. in Tables 1 to 11), as well as the siRNAs themselves that inhibits the expression of an endogenous gene.
The invention provides for double-stranded RNAi agents capable of inhibiting the expression of a target gene in vivo. The RNAi agent may comprise a sense strand and an antisense strand. Each strand of the RNAi agent may range from 12-30 nucleotides in length. For example, each strand may be between 14-30 nucleotides in length, 17-30 nucleotides in length, 25-30 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length.
The sense strand and antisense strand typically form a duplex double stranded RNA (“dsRNA”). The duplex region of an RNAi agent may be 12-30 nucleotide pairs in length. For example, the duplex region can be between 14-30 nucleotide pairs in length, 17-30 nucleotide pairs in length, 27-30 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length. In another example, the duplex region is selected from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotides in length.
In some embodiments, an inhibitory nucleic acid is a dicer small interfering RNA (dsiRNA). As used herein, ‘dsiRNA’ refers to a double-stranded RNA molecule having a length of ˜27 base pairs, which is processed by Dicer to siRNA for RNAi-mediated degradation of target RNA. DsiRNAs are described e.g. in Raja et al., Asian J Pharm Sci. (2019) 14(5): 497-510, which is hereby incorporated by reference in their entirety. DsiRNAs are optimised for Dicer processing and may have increased potency compared with 21-mer siRNAs (see e.g. Kim et al., Nat Biotechnol. (2005) 23(2):222-226), which may be related to the link between Dicer-mediated nuclease activity and RISC loading.
In some embodiments, an inhibitory nucleic acid is a micro RNA (miRNA), or a precursor thereof (e.g. a pri-miRNA or a pre-miRNA). miRNA molecules have a similar structure to siRNA molecules, but are encoded endogenously, and derived from processing of short hairpin RNA molecules. They are initially expressed as long primary transcripts (pri-miRNAs), which are processed within the nucleus into 60 to 70 nucleotide hairpins (pre-miRNAs), which are further processed in the cytoplasm into smaller species that interact with RISC and target mRNA. miRNAs comprise ‘seed sequences’ that are essential for binding to target mRNA. Seed sequences usually comprise six nucleotides and are situated at positions 2 to 7 at the miRNA 5′ end.
In some embodiments, an inhibitory nucleic acid is a short hairpin RNA (shRNA), e.g. as provided in Tables 12 and 13 (showing sense-loop-antisense sequences). shRNA molecules comprise sequences of nucleotides having a high degree of complementarity that associate with one another through complementary base pairing to form the stem region of the hairpin. The sequences of nucleotides having a high degree of complementarity may be linked by one or more nucleotides that form the loop region of the hairpin. shRNA molecules may be processed (e.g. via catalytic cleavage by DICER) to form siRNA or miRNA molecules. shRNA molecules may have a length of between 35 to 100 (e.g. 40 to 70) nucleotides. The stem region of the hairpin may have a length between 17 to 30 (e.g. 20 to 27, e.g. ˜21-23) base pairs. The stem region may comprise G-U pairings to stabilise the hairpin structure. An shRNA sequence described herein may comprise sequences that will be subsequently processed into shorter siRNA strand(s), such as the guide/passenger strands presented in Tables 1-11.
siRNA, dsiRNA, miRNAs and shRNAs for the targeted inhibition of gene and/or protein expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB may be identified/designed in accordance with principles and/or using tools well known to the skilled person. Parameters and tools for designing siRNA and shRNA molecules are described e.g. in Fakhr et al., Cancer Gene Therapy (2016) 23:73-82 (hereby incorporated by reference in its entirety). Software that may be used by the skilled person for the design of such molecules is summarised in Table 1 of Fakhr et al., Cancer Gene Therapy (2016) 23:73-82, and includes e.g. siRNA Wizard (InvivoGen). Details for making such molecules can be found in the websites of commercial vendors such as Ambion, Dharmacon, GenScript, Invitrogen and OligoEngine.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of any one or more of SEQ ID NOs: 1 to 7091, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to one of SEQ ID NOs: 1 to 7091; and (ii) nucleic acid comprising a nucleotide sequence having the reverse complement of the nucleotide sequence of (i), or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to the reverse complement of the nucleotide sequence of (i). SEQ ID NOs 1 to 7091 are displayed in Tables 1 to 10 provided herein. The nucleic acid according to the present disclosure may be capable of reducing gene and/or protein expression of any one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB, according to the heading of the Table in which the SEQ ID NO is presented. For example, a SEQ ID NO presented in Table 2 may be capable of reducing gene and/or protein expression of MFAP4.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of any one or more of SEQ ID NOs: 7092 to 7096, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to one of SEQ ID NOs: 7092 to 7096; and (ii) nucleic acid comprising a nucleotide sequence having the reverse complement of the nucleotide sequence of (i), or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to the reverse complement of the nucleotide sequence of (i).
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of SEQ ID NO: 7092, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7092; and (ii) nucleic acid comprising a nucleotide sequence of SEQ ID NO: 7141, or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7141.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of SEQ ID NO: 7093, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7093; and (ii) nucleic acid comprising a nucleotide sequence of SEQ ID NO: 7142, or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7142.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of SEQ ID NO: 7094, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7094; and (ii) nucleic acid comprising a nucleotide sequence of SEQ ID NO: 7143, or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7143.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of SEQ ID NO: 7095, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7095; and (ii) nucleic acid comprising a nucleotide sequence of SEQ ID NO: 7144, or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7144.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of SEQ ID NO: 7096, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7096; and (ii) nucleic acid comprising a nucleotide sequence of SEQ ID NO: 7145, or having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7145.
In some embodiments in accordance with the preceding seven paragraphs, the nucleotide sequence of (i) and the nucleotide sequence of (ii) may be provided on different nucleic acids (i.e. separate oligonucleotides). As such, the nucleic acid of (i) and (ii) may be different nucleic acids. In such embodiments, the inhibitory nucleic acid may comprise or consist of a nucleic acid duplex formed by complementary base pairing between the different nucleic acids comprising the nucleotide sequences of (i) and (ii).
Alternatively, in some embodiments the nucleotide sequence of (i) and the nucleotide sequence of (ii) may be provided on the same nucleic acid (i.e. a single oligonucleotide). That is, the nucleic acid of (i) and (ii) may be the same nucleic acid. In such embodiments, the nucleotide sequence of (i) and the nucleotide sequence of (ii) may be connected by one or more linker nucleotides. The inhibitory nucleic acid may comprise a nucleic acid duplex region formed by complementary base pairing between the nucleotide sequences of (i) and (ii), and the linker regions may form a single-stranded loop region.
Disclosed herein is a nucleic acid inhibitor consisting, comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in any of Tables 1 to 13 (or any combination of Tables thereof) or an RNAi agent that hybridizes to the complement of an RNA sequence listed in any of Tables 1 to 13 (or any combination of Tables thereof) under stringency conditions.
Disclosed herein is a nucleic acid inhibitor consisting, comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in any of Tables 2-12 (or any combination of Tables thereof) or an RNAi agent that hybridizes to the complement of an RNA sequence listed in any of Tables 2-12 (or any combination of Tables thereof) under stringency conditions.
Disclosed herein is a nucleic acid inhibitor consisting, comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in Table 1 or 13, or an RNAi agent that hybridizes to the complement of an RNA sequence listed in Table 1 or 13 under stringency conditions.
The terms “nucleic acid” and “polynucleotide’, used interchangeably herein, refer to polymeric forms of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, these terms include, but are not limited to, single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. These terms further include, but are not limited to, mRNA or cDNA that comprise intronic sequences. The backbone of the polynucleotide can comprise sugars and phosphate groups (as may typically be found in RNA or DNA), or modified or substituted sugar or phosphate groups. Alternatively, the backbone of the polynucleotide can comprise a polymer of synthetic subunits such as phosphoramidites and thus can be an oligodeoxynucleoside phosphoramidate or a mixed phosphoramidate-phosphodiester oligomer. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, uracyl, other sugars, and linking groups such as fluororibose and thioate, and nucleotide branches. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications included in this definition are caps, substitution of one or more of the naturally occurring nucleotides with an analog, and introduction of means for attaching the polynucleotide to proteins, metal ions, labeling components, other polynucleotides, or a solid support. The term “polynucleotide” also encompasses peptidic nucleic acids, PNA and LNA. Polynucleotides may further comprise genomic DNA, cDNA, or DNA-RNA hybrids.
The term “RNA” or “RNA molecule” or “ribonucleic acid molecule” refers to a polymer of ribonucleotides. The term “DNA” or “DNA molecule” or deoxyribonucleic acid molecule” refers to a polymer of deoxyribonucleotides. DNA and RNA can be synthesized naturally (e.g., by DNA replication or transcription of DNA, respectively). RNA can be post-transcriptionally modified. DNA and RNA can also be chemically synthesized. DNA and RNA can be single-stranded (i.e., ssRNA and ssDNA, respectively) or multi-stranded (e.g., double stranded, i.e., dsRNA and dsDNA, respectively). “mRNA” or “messenger RNA” is single-stranded RNA that specifies the amino acid sequence of one or more polypeptide chains. This information is translated during protein synthesis when ribosomes bind to the mRNA.
“Stringency conditions” refers to conditions under which a nucleic acid may hybridize to its target polynucleotide sequence, but not other sequences. Stringent conditions are sequence-dependent (e.g., longer sequences hybridize specifically at higher temperatures). Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH, and polynucleotide concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Typically, stringent conditions will be those in which the salt concentration is at least about 0.01 to about 1.0 M sodium ion concentration (or other salts) at about pH 7.0 to about pH 8.3 and the temperature is at least about 30° C. for short probes (e.g., 10 to 50 nucleotides).
As used herein, the term “complement” when used in reference to a nucleic acid sequence refers to the complementary sequence of the nucleic acid sequence as dictated by base-pairing, but in reverse orientation so as to result in complementarity upon fold-over into a hairpin structure. The term encompasses partial complementarity where only some of the bases are matched according to base pairing rules as well as total complementarity between the two nucleic acid sequences.
Modifications
Nucleic acid inhibitors/inhibitory nucleic acids according to the present disclosure may comprise chemically modified nucleotide acids, e.g. in which the phosphonate and/or ribose and/or base is/are chemically modified. Such modifications may influence the activity, specificity and/or stability of nucleic acid. One or more (e.g. one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or all) nucleotides of a nucleic acid inhibitor may comprise such chemical modification.
Modifications contemplated in accordance with nucleic acid inhibitors according to the present disclosure include those described in Hu et al., Sig. Transduc. Tar. Ther. (2020) 5(101) (incorporated by reference hereinabove), in particular those shown in FIG. 2 of Hu et al., Sig. Transduc. Tar. Ther. (2020) 5(101). Further modifications contemplated in accordance with nucleic acid inhibitors according to the present disclosure include those described in Selvam et al., Chem Biol Drug Des. (2017) 90(5): 665-678, which is hereby incorporated by reference in its entirety).
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises one or more nucleotides comprising a phosphonate modification. In some embodiments, the phosphonate modification(s) may be selected from: phosphorothioate (e.g. Rp isomer, Sp isomer), phosphorodithioate, methylphosphonate, methoxypropylphosphonate, 5′-(E)-vinylphosphonate, 5′-methylphosphonate, (S)-5′-C-methyl with phosphate, 5′-phosphorothioate, and peptide nucleic acid. In some embodiments, aa nucleic acid inhibitor comprises one or more nucleotides comprising phosphorothioate modification.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises one or more nucleotides comprising a ribose modification. In some embodiments, the ribose modification(s) may be selected from: 2′-O-methyl, 2′-O-methoxyethyl, 2′-fluoro, 2′-deoxy-2′-fluoro, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C-allyl, 2′-deoxy, 2′-hydroxyl, 2′-arabino-fluoro, 2′-O-benzyl, 2′-O-methyl-4-pyridine, locked nucleic acid, (S)-cEt-BNA, tricyclo-DNA, PMO, unlocked nucleic acid, hexitol nucleic acid and glycol nucleic acid. In some embodiments, an inhibitory nucleic acid comprises one or more nucleotides comprising 2′-O-methyl modification. In some embodiments, an inhibitory nucleic acid comprises one or more nucleotides comprising 2′-fluoro modification.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises one or more nucleotides comprising a base modification. In some embodiments, the base modification(s) may be selected from: pseudouridine, 2′-thiouridine, N6′-methyladenosine, 5′-methylcytidine, 5′-fluoro-2′-deoxyuridine, N-ethylpiperidine 7′-EAA triazole-modified adenine, N-ethylpiperidine 6′-triazole-modified adenine, 6′-phenylpyrrolo-cytosine, 2′,4′-difluorotoluyl ribonucleoside and 5′-nitroindole.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: one or more nucleotides comprising phosphorothioate modification, one or more nucleotides comprising 2′-O-methyl modification, and one or more nucleotides comprising 2′-fluoro modification.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises one or more modified nucleotides selected from: 2′-O-methyluridine-3′-phosphate, 2′-O-methyladenosine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methyluridine-3′-phosphorothioate, 2′-O-methyladenosine-3′-phosphorothioate, 2′-O-methylguanosine-3′-phosphorothioate, 2′-O-methylcytidine-3′-phosphorothioate, 2′-fluorouridine-3′-phosphate, 2′-fluoroadenosine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluorocytidine-3′-phosphorothioate, 2′-fluoroguanosine-3′-phosphorothioate, 2′-fluoroadenosine-3′-phosphorothioate, and 2′-fluorouridine-3′-phosphorothioate.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises a nucleotide sequence comprising 3 to 10 (e.g. one of 3, 4, 5, 6, 7, 8, 9 or 10) nucleotides comprising 2′-fluoro modification. In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises 4 to 15 (e.g. one of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) nucleotides comprising 2′-fluoro modification. In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises a nucleotide sequence comprising 2 to 6 (e.g. one of 2, 3, 4, 5 or 6) nucleotides comprising phosphorothioate modification. In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises 5 to 20 (e.g. one of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) nucleotides comprising 2′-O-methyl modification. In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises a nucleotide sequence comprising 2 to 6 (e.g. one of 2, 3, 4, 5 or 6) nucleotides comprising 2′-O-methyl and phosphorothioate modification. In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises a nucleotide sequence comprising 1 to 4 (e.g. one of 1, 2, 3 or 4) nucleotides comprising 2′-fluoro and phosphorothioate modification.
In embodiments wherein nucleic acid inhibitors/inhibitory nucleic acids comprise nucleotides comprising chemical modification as described herein, the nucleotide sequence is nevertheless evaluated for the purposes of sequence comparison in accordance with the present disclosure as if the equivalent unmodified nucleotide were instead present.
Nucleic acids comprising nucleotide(s) comprising a modified phosphonate group are evaluated for the purposes of nucleotide sequence comparison as if nucleotide(s) comprising a modified phosphonate group instead comprise the equivalent unmodified phosphonate group. Nucleic acids comprising nucleotide(s) comprising a modified ribose group are evaluated for the purposes of nucleotide sequence comparison as if nucleotide(s) comprising a modified ribose group instead comprise the equivalent unmodified ribose group. Nucleic acids comprising nucleotide(s) comprising a modified base group are evaluated for the purposes of nucleotide sequence comparison as if nucleotide(s) comprising a modified base group instead comprise the equivalent unmodified base group.
By way of illustration, nucleic acids comprising nucleotides comprising pseudouridine, 2-thiouridine and/or 5′-fluoro-2′-deoxyuridine are evaluated for the purposes of nucleotide sequence comparison as if nucleotides comprising uridine were instead present at their respective positions. By way of illustration, nucleic acids comprising nucleotides comprising N6′-methyladenosine, N-ethylpiperidine 7′-EAA triazole-modified adenine and/or N-ethylpiperidine 6′-triazole-modified adenine are evaluated for the purposes of nucleotide sequence comparison as if nucleotides comprising adenine were instead present at their respective positions. By way of illustration, nucleic acids comprising nucleotides comprising 5′-methylcytidine and/or 6′-phenylpyrrolo-cytosine are evaluated for the purposes of nucleotide sequence comparison as if nucleotides comprising cytosine were instead present at their respective positions.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in Table 11.
In some embodiments, an inhibitory nucleic acid comprises nucleic acid comprising the nucleotide sequence (including the modifications thereto) shown in any one or more of SEQ ID NOs: 7146 to 7155 of Table 11. The following six paragraphs refer to SEQ ID NOs presented in Table 11.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of any one of SEQ ID NOs: 7146 to 7150, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to one of SEQ ID NOs: 7146 to 7150; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of any one of SEQ ID NOs: 7151 to 7155, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to one of SEQ ID NOs: 7151 to 7155.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7146, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7146; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7151, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7151.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7147, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7147; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7152, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7152.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7148, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7148; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7153, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7153.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7149, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7149; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7154, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7154.
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7150, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7150; and (ii) nucleic acid comprising the nucleotide sequence (including the modifications thereto) of SEQ ID NO: 7155, or a nucleotide sequence (including the modifications thereto) having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to SEQ ID NO: 7155.
In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims.
In one embodiment, each residue of the sense strand and antisense strand is independently modified with LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-deoxy, 2′-hydroxyl, or 2′-fluoro. The strands can contain more than one modification.
Inhibitory nucleic acids according to the present disclosure may be produced in accordance with techniques well known to the skilled person.
For example, inhibitory nucleic acids may be produced recombinantly by transcription of a nucleic acid sequence encoding the inhibitory nucleic acid. A nucleic acid encoding an inhibitory nucleic acid according to the present disclosure may e.g. be contained within an expression vector for expression of the inhibitory nucleic acid.
Transcription may be performed in cell-free transcription reactions using recombinant enzymes (e.g. RNA polymerase) for transcription of the inhibitory nucleic acids. Alternatively, production of an inhibitory nucleic acid according to the present disclosure may be performed in a cell comprising nucleic acid encoding the inhibitory nucleic acid, and may employ cellular enzymes (e.g. RNA polymerase) for transcription. Production of an inhibitory nucleic acid according to the present disclosure by expression within a cell may comprise transcription from a vector. Introduction of nucleic acid/vectors for the purposes of production of inhibitory nucleic acids according to the present disclosure may be performed in any of the ways known in the art (e.g. transfection, transduction, electroporation, etc.). Expression of an inhibitory nucleic acid can be regulated using a cell-specific promoter (e.g. a liver cell-specific promoter).
For example, an shRNA molecule according to the present disclosure may be produced within a cell by transcription from a vector encoding the shRNA. shRNAs may be produced within a cell by transfecting the cell with a vector encoding the shRNA sequence under control of an RNA polymerase promoter.
An siRNA molecule according to the present disclosure may be produced within a cell by transcription from a vector encoding shRNA encoding/comprising the siRNA, and subsequent processing of the shRNA molecule by cellular DICER to form the siRNA molecule. An shRNA molecule according to the present disclosure, e.g. a sequence in Table 12 or 13, may be embedded into and expressed using a miR-30-based system, e.g. as described in Fellmann C et al., Cell Rep. 2013; 5(6):1704-13, and Rio D C et al., Cold Spring Harb Protoc; 2013; doi:10.1101/pdb.prot075853, which are hereby incorporated by reference in their entirety.
Inhibitory nucleic acids may also be synthesised using standard solid or solution phase synthesis techniques which are well known in the art. Solid phase synthesis may use phosphoramidite chemistry. Briefly, a solid supported nucleotide may be detritylated, then coupled with a suitably activated nucleoside phosphoramidite to form a phosphite triester linkage. Capping may then occur, followed by oxidation of the phosphite triester with an oxidant, typically iodine. The cycle may then be repeated to yield a polynucleotide.
The present disclosure provides nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure. In some embodiments, nucleic acid comprising or encoding an inhibitory nucleic acid comprises, or consists of, DNA and/or RNA.
The present disclosure also provides a vector comprising the nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure.
Nucleic acids and vectors according to the present disclosure may be provided in purified or isolated form, i.e. from other nucleic acid, or naturally-occurring biological material.
The nucleotide sequence of a nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure may be contained in a vector, e.g. an expression vector. A ‘vector’ as used herein is a nucleic acid molecule used as a vehicle to transfer exogenous nucleic acid into a cell. The vector may be a vector for expression of the nucleic acid in the cell. Such vectors may include a promoter sequence operably linked to the nucleotide sequence encoding the sequence to be expressed. A vector may also include a termination codon and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express nucleic acid from a vector according to the present disclosure.
The term ‘operably linked’ may include the situation where a selected nucleic acid sequence and regulatory nucleic acid sequence (e.g. promoter and/or enhancer) are covalently linked in such a way as to place the expression of nucleic acid sequence under the influence or control of the regulatory sequence (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to the selected nucleic acid sequence if the regulatory sequence is capable of affecting transcription of the nucleic acid sequence.
Suitable vectors include plasmids, binary vectors, DNA vectors, mRNA vectors, viral vectors (e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors), lentiviral vectors, adenovirus vectors, adeno-associated virus vectors, vaccinia virus vectors and herpesvirus vectors), transposon-based vectors, and artificial chromosomes (e.g. yeast artificial chromosomes).
In some embodiments, the vector may be a eukaryotic vector, e.g. a vector comprising the elements necessary for expression of nucleic acid from the vector in a eukaryotic cell. In some embodiments, the vector may be a mammalian vector, e.g. comprising a cytomegalovirus (CMV) or SV40 promoter to drive expression. In some embodiments, the vector comprises a cell- or tissue-specific promoter. In some embodiments, the vector comprises a liver cell-specific promoter.
The present disclosure also provides a plurality of inhibitory nucleic acids according to the present disclosure. The present disclosure also provides nucleic acids and vectors comprising or encoding a plurality of inhibitory nucleic acids according to the present disclosure.
Individual inhibitory nucleic acids of a plurality of inhibitory nucleic acids according to the present disclosure may be identical or non-identical. Similarly, in embodiments wherein a nucleic acid/vector comprising or encoding an inhibitory nucleic acid according to the present disclosure comprises/encodes more than one inhibitory nucleic acid according to the present disclosure, the inhibitory nucleic acids comprised/encoded by the nucleic acid/vector may be identical or non-identical.
In some embodiments, nucleic acids/vectors may encode one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 inhibitory nucleic acids according to the present disclosure. In some embodiments, nucleic acids/vectors may encode multiple (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) copies of a given inhibitory nucleic acid according to the present disclosure.
In some embodiments, a plurality of inhibitory nucleic acids according to the present disclosure may be a plurality of non-identical inhibitory nucleic acids. In some embodiments, a plurality of inhibitory nucleic acids may comprise one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 non-identical inhibitory nucleic acids. In some embodiments, nucleic acids/vectors may comprise/encode a plurality of non-identical inhibitory nucleic acids according to the present disclosure.
The following two paragraphs further define pluralities of non-identical inhibitory nucleic acids in accordance with embodiments of pluralities of inhibitory nucleic acids according to the present disclosure, and also in accordance with embodiments of nucleic acids/vectors comprising/encoding a plurality of non-identical inhibitory nucleic acids according to the present disclosure.
In some embodiments, the non-identical inhibitory nucleic acids comprise or encode non-identical antisense nucleic acids. In such embodiments, the non-identical antisense nucleic acids may each independently conform to any embodiment of an antisense nucleic acid as described hereinabove.
In some embodiments, the non-identical inhibitory nucleic acids may comprise or encode antisense nucleic acids targeting non-identical target nucleotide sequences. In such embodiments, the non-identical target nucleotide sequences may each independently conform to any embodiment of a target nucleotide sequence for an antisense nucleic acid as described hereinabove.
The present disclosure also provides a cell comprising or expressing (i) an inhibitory nucleic acid according to the present disclosure, (ii) nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure, and/or (iii) a vector comprising nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure.
The cell may be a eukaryotic cell, e.g. a mammalian cell. The mammal may be a primate (rhesus, cynomolgous, non-human primate or human) or a non-human mammal (e.g. rabbit, guinea pig, rat, mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cows, e.g. dairy cows, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate). In preferred embodiments, the cell may be a human cell. In some embodiments, the cell may be a liver cell.
The present disclosure also provides a method for producing a cell comprising a nucleic acid or vector according to the present disclosure, comprising introducing a nucleic acid or vector according to the present disclosure into a cell. In some embodiments, introducing a nucleic acid or vector according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. retroviral transduction).
The present disclosure also provides a method for producing an inhibitory nucleic acid according to the present disclosure or a nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure, comprising culturing a cell comprising nucleic acid comprising or encoding an inhibitory nucleic acid according to the present disclosure or a vector according to the present disclosure under conditions suitable for expression of the nucleic acid or vector by the cell. In some embodiments, the methods are performed in vitro.
The present disclosure also provides compositions comprising nucleic acids (including inhibitory nucleic acids, nucleic acids comprising/encoding an inhibitory nucleic acid, expression vectors comprising/encoding such nucleic acids) or cells according to the present disclosure.
In therapeutic and prophylactic applications, the inhibitors and compositions of the present disclosure are preferably formulated as a medicament or pharmaceutical composition (suitable for clinical use). Such compositions may comprise the inhibitor or cell together with one or more other pharmaceutically-acceptable ingredients well known to those skilled in the art. Such ingredients include, but are not limited to, pharmaceutically-acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
Provided herein is a pharmaceutical composition comprising an inhibitor as defined herein and a pharmaceutically acceptable carrier.
Compositions according to the present disclosure may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
The compositions may be prepared for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intravitreal, intraconjunctival, subretinal, suprachoroidal, subcutaneous, intradermal, intrathecal, oral, nasal or transdermal routes of administration which may include injection or infusion. Suitable formulations may comprise the selected agent in a sterile or isotonic medium. The formulation and mode of administration may be selected according to the agent to be administered, and disease to be treated/prevented.
The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including intranasal or intrapulmonary), oral or parenteral. Parenteral administration includes intravenous, subcutaneous, intraperitoneal or intramuscular injection.
The compositions of the present disclosure may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via catheter) to a selected organ or region of the human or animal body. A further aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition according to the present disclosure, the method comprising formulating a pharmaceutical composition or medicament by mixing an agent with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.
Delivery of Inhibitors
Inhibitors (including e.g. small molecules, antibodies and nucleic acids (including inhibitory nucleic acids, expression vectors)), cells and compositions according to the present disclosure may be modified and/or be formulated to facilitate delivery to, and/or uptake by, a cell/tissue of interest, e.g. a liver cell (hepatocyte) or hepatic tissue.
Strategies for targeted delivery of such species are reviewed e.g. in Li et al., Int. J. Mol. Sci. (2015) 16: 19518-19536 and Fu et al., Bioconjug Chem. (2014) 25(9): 1602-1608, which are hereby incorporated by reference in their entirety. In particular, nucleic acids according to the present disclosure may employ a delivery platform described in Hu et al., Sig. Transduc. Tar. Ther. (2020) 5(101) (incorporated by reference hereinabove), or Tatiparti et al. ‘siRNA Delivery Strategies: A Comprehensive Review of Recent Developments.’ Ed. Thomas Nann. Nanomaterials 7.4 (2017): 77, and Lehto T et al., Adv Drug Deliv Rev. 2016, 106(Pt A):172-182, which are hereby incorporated by reference in their entirety.
In some embodiments, articles of the present disclosure may be encapsulated in a nanoparticle or a liposome. In some embodiments, articles of the present disclosure may be (covalently or non-covalently) associated with a cell-penetrating peptide (e.g. a protein transduction domain, trojan peptide, arginine-rich peptide, vectocell peptide), a cationic polymer, a cationic lipid or a viral carrier.
Nanoparticles may be organic, e.g. micelles, liposomes, proteins, solid-lipid particles, solid polymer particles, dendrimers, and polymer therapeutics. Nanoparticles may be inorganic, e.g. such as nanotubes or metal particles, optionally with organic molecules added. In some embodiments, a nanoparticle is a nanoparticle described in Chen et al., Mol Ther Methods Clin Dev. (2016) 3:16023, which is hereby incorporated by reference in its entirety. In some embodiments, a nanoparticle is a PLGA, polypeptide, poly(β-amino ester), DOPE, β-cyclodextrin-containing polycation, linear PEI, PAMAM dendrimer, branched PEI, chitosan or polyphosophoester nanoparticle.
The delivery of a nucleic acid inhibitor, e.g. an RNAi agent, to a cell e.g., a cell within a subject, such as a human subject can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with a nucleic acid of the invention either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising a nucleic acid inhibitor, e.g., a siRNA, shRNA, dsRNA, to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors (e.g. one or more DNA vectors) that encode and direct the expression of the nucleic acid inhibitor. In one embodiment, the nucleic acid inhibitor is delivered using a viral-based or transposon-based nucleic acid construct. In one embodiment, the nucleic acid inhibitor is encapsulated in a liposome.
In some embodiments, an inhibitor according to the present disclosure (e.g. a small molecule, a peptide, an antibody, an inhibitory nucleic acid, a nucleic acid comprising/encoding an inhibitory nucleic acid, or an expression vector) comprises modification to incorporate one or more moieties facilitating delivery to, and/or uptake by, a cell type or tissue of interest. In some embodiments, an inhibitor according to the present disclosure is linked (e.g. chemically conjugated to) one or more moieties facilitating delivery to, and/or uptake by, a cell type or tissue of interest.
Modification to, and formulation of, inhibitors to facilitate targeted delivery to cell types and/or tissues of interest is described e.g. in Lorenzer et al., J Control Release (2015) 203:1-15, which is hereby incorporated by reference in its entirety. The moiety facilitating delivery to, and/or uptake by, a cell type or tissue of interest may bind selectively to the target cell type/tissue of interest. The moiety may facilitate traversal of the cell membrane of the target cell type and/or of cells of the tissue of interest. The moiety may bind to a molecule expressed at the cell surface of the target cell type/tissue of interest. The moiety may facilitate internalisation of the nucleic acid by the target cell type/tissue of interest (e.g. by endocytosis).
Moieties facilitating delivery to, and/or uptake by, cell types or tissues of interest are described e.g. in Benizri et al., Bioconjug Chem. (2019) 30(2): 366-383, which is hereby incorporated by reference in its entirety. Such moieties include e.g. N-acetylgalactosamine (GalNAc), α-tocopherol, cell-penetrating peptide, nucleic acid aptamer, antibody and antigen-binding fragments/derivatives thereof, cholesterol, squalene, polyethylene glycol (PEG), fatty acid (e.g. palmitic acid) and nucleolipid moieties.
In some embodiments, the moiety may e.g. be a peptide/polypeptide (e.g. an antibody, fragment or derivative thereof, peptide aptamer or cell-penetrating peptide) or nucleic acid (e.g. a nucleic acid aptamer) which binds to the target cell type/tissue of interest, e.g. via interaction with a molecule expressed at the cell surface of the target cell type/tissue of interest.
In some embodiments, a nucleic acid according to the present disclosure comprises a moiety facilitating delivery to, and/or uptake by, a liver cell (e.g. a hepatocyte) and/or hepatic tissue. In such embodiments, the moiety may facilitate traversal of the hepatocyte cell membrane. The moiety may bind to a molecule expressed at the cell surface of hepatocytes. In some embodiments, a molecule expressed at the cell surface of hepatocytes is an asialoglycoprotein receptor, e.g. ASGR1 or ASGR2. The moiety may facilitate internalisation of a nucleic acid by hepatocytes (e.g. by endocytosis).
In some embodiments, the moiety may e.g. be a peptide/polypeptide (e.g. an antibody, fragment or derivative thereof, peptide aptamer or cell-penetrating peptide) or nucleic acid (e.g. a nucleic acid aptamer) which binds to a hepatocyte and/or hepatic tissue, e.g. via interaction with a molecule expressed at the cell surface of a hepatocyte (e.g. an asialoglycoprotein receptor, e.g. ASGR1 or ASGR2).
In some embodiments, the moiety is, or comprises, GalNAc. In some embodiments, an inhibitor, e.g. a nucleic acid, is conjugated to GalNAc. GalNAc interacts with asialoglycoprotein receptors expressed by hepatocytes. Nucleic acids conjugated to GalNAc are efficiently internalised by hepatic cells via receptor-mediated endocytosis following binding of GalNAc to ASGPR (see e.g. Nair et al., J. Am. Chem. Soc. (2014) 136(49): 16958-16961). In some embodiments, an inhibitor, e.g. a nucleic acid, is conjugated to one or more (e.g. 1, 2, 3, 4 or more) GalNAc moieties. In some embodiments, one or more GalNAc moieties may be covalently associated to the 5′ or 3′ end of one or more strands of a nucleic acid. In some embodiments, a nucleic acid is conjugated to a triantennary GalNAc carbohydrate moiety (such moieties are described e.g. in Nair et al., supra).
In some embodiments, an inhibitory nucleic acid according to the present disclosure comprises: (i) nucleic acid comprising the nucleotide sequence of one of SEQ ID NOs: 1 to 7155, or a nucleotide sequence having at least 75% sequence identity (e.g. one of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity) to one of SEQ ID NOs: 1 to 7155; and (ii) a triantennary GalNAc carbohydrate moiety.
In some embodiments, the moiety is, or comprises, α-tocopherol (i.e. vitamin E). In some embodiments, a nucleic acid is conjugated to α-tocopherol. Nucleic acid-α-tocopherol conjugates have been employed for targeted delivery of nucleic acids to the liver (see e.g. Nishina et al., Mol Ther. (2008) 16(4):734-740). In some embodiments, a nucleic acid is conjugated to one or more (e.g. 1, 2, 3, 4 or more) α-tocopherol moieties. In some embodiments, one or more α-tocopherol moieties may be covalently associated to the 5′ or 3′ end of one or more strands of a nucleic acid.
Conjugates of biomolecules may be produced utilising ‘click chemistry’, as described e.g. in Nwe and Brechbiel Cancer Biother Radiopharm. (2009) 24(3):289-302 and Astakhova et al., Mol Pharm. (2018) 15(8): 2892-2899, both of which are hereby incorporated by reference in their entirety. In some embodiments, conjugation may employ akyne-azide or thio-maleimide approaches. In some embodiments, an inhibitor, e.g. nucleic acid, may be conjugated to a moiety facilitating delivery to, and/or uptake by, a cell type or tissue of interest, e.g. at the 3′ and/or 5′ end of one or more strands of the nucleic acid.
Inhibitors may be conjugated to one or more moieties facilitating delivery to, and/or uptake by, cell types or tissues of interest via a linker. In some embodiments, a linker may be or comprise a nucleotide sequence. The nucleotide sequence of a linker may comprise one or more modified nucleotides as described herein.
Treatment/Prevention of Disease
The inhibitors, nucleic acids, expression vectors, cells and compositions described herein find use in therapeutic and prophylactic methods.
The present invention provides methods and articles (agents and compositions) for the treatment and/or prevention of diseases through inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. Treatment/prevention of disease is achieved by inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in e.g. a cell, tissue/organ/organ system/subject.
The invention is concerned with the treatment and/or prevention of diseases which are caused and/or exacerbated by an increase in the expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (and/or associated downstream factors), or diseases which are caused and/or exacerbated by a decrease in the expression/activity of one or more associated downstream factors that are downregulated by one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Inhibition of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (genes, mRNA and/or proteins) in any of the methods described herein may be achieved using any suitable inhibitor. In some embodiments, the inhibitor is a nucleic acid, peptide, antibody, antigen-binding molecule or small molecule inhibitor, e.g. as described herein. Multiple inhibitors may be used to target any two or more of the genes/proteins.
In any method provided herein, the inhibitor may be a nucleic acid as described herein, e.g. an inhibitory nucleic acid.
The utility of the present invention extends to the treatment/prevention of any disease that would derive therapeutic/prophylactic benefit from a reduction in the level of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB expression and/or activity.
In some embodiments, a disease to be treated/prevented may be characterised by an increase in the expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (or a correlate thereof) in an organ/tissue/subject affected by the disease e.g. as compared to normal organ/tissue/subject (i.e. in the absence of the disease).
Treatment/prevention may be of a disease that is associated with an upregulation in the expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (or a correlate thereof) in cells/tissue/an organ in which the symptoms of the disease manifest.
The experimental examples demonstrate that expression of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and LTB is upregulated in fibroinflammatory disorders, such as liver disease, inflammatory liver disorders, steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).
Thus, the present disclosure establishes inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, or LTB as being useful for the treatment/prevention of diseases that are characterised by, e.g., NAFLD, NASH, fibrosis, and/or inflammation, e.g. of the liver or other tissues.
Aspects of the present invention are concerned with the treatment/prevention of a liver disease or condition.
Thus, in one aspect the present invention provides a method of treating or preventing a liver disease or condition, comprising inhibiting at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. As described hereinabove, inhibition/inhibiting may refer to inhibition of the expression and/or activity of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB and the downstream functional consequences thereof, and encompasses decreased/reduced gene and/or protein expression or decreased/reduced activity of any one of said genes/proteins.
Also provided is a method of treating or preventing a liver disease or condition, comprising administering a therapeutically or prophylactically effective amount of an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to a subject. The method may comprise administering two or more (i.e. 2, 3, 4, 5, 6, 7, 8 or 9) inhibitors that target two or more (i.e. 2, 3, 4, 5, 6, 7, 8 or 9) of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Also provided is an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB for use in a method of treating or preventing a liver disease or condition.
Also provided is the use of an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in the manufacture of a medicament for use in a method of treating or preventing a liver disease or condition.
The inhibitor may be any suitable inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, such as any agent described herein, e.g. nucleic acid, peptide, antibody, antigen-binding molecule or small molecule inhibitor. In some embodiments the inhibitor is an inhibitory nucleic acid, such as those described herein.
In some embodiments, the liver disease or condition to be treated/prevented is selected from the group consisting of: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, mild liver fibrosis, advanced liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (ALFD), alcohol-related liver disease (ARLD), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), hepatitis, liver damage, liver injury, liver failure, metabolic syndrome, obesity, diabetes mellitus, end-stage liver disease, inflammation of the liver, lobular inflammation, and/or hepatocellular carcinoma (HCC).
In some embodiments, the liver fibrosis is a virus-induced liver fibrosis. In some embodiments, the hepatitis is an alcohol-induced hepatitis. In some embodiments, the liver damage is a drug or virus-induced liver damage.
The experimental examples of the present disclosure identify MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and LTB as regulators of fibroinflammatory processes, which are moreover conserved between different tissue types.
Aspects of the present invention are concerned with the treatment/prevention of diseases in which profibrotic processes are pathologically implicated. Accordingly, in some embodiments the disease is fibrosis, or a disease characterised by fibrosis.
As used herein, “fibrosis” refers to the formation of excess fibrous connective tissue as a result of the excess deposition of extracellular matrix components, for example collagen. Fibrous connective tissue is characterised by having extracellular matrix (ECM) with a high collagen content. The collagen may be provided in strands or fibers, which may be arranged irregularly or aligned. The ECM of fibrous connective tissue may also include glycosaminoglycans.
As used herein, “excess fibrous connective tissue” refers to an amount of connective tissue at a given location (e.g. a given tissue or organ, or part of a given tissue or organ) which is greater than the amount of connective tissue present at that location in the absence of fibrosis, e.g. under normal, non-pathological conditions. As used herein, “excess deposition of ECM components” refers to a level of deposition of one or more ECM components which is greater than the level of deposition in the absence of fibrosis, e.g. under normal, non-pathological conditions.
The cellular and molecular mechanisms of fibrosis are described in Wynn, J. Pathol. (2008) 214(2): 199-210, and Wynn and Ramalingam, Nature Medicine (2012) 18:1028-1040, which are hereby incorporated by reference in their entirety.
Damage to tissues can result from various stimuli, including infections, autoimmune reactions, toxins, radiation and mechanical injury. Repair typically involves replacement of injured cells by cells of the same type, and replacement of normal parenchymal tissue with connective tissue. Repair processes become pathogenic when they are not controlled properly, resulting in substantial deposition of ECM components in which normal tissue is replaced with permanent scar tissue. In diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, cardiovascular fibrosis, systemic sclerosis and nephritis, extensive tissue remodelling and fibrosis can ultimately lead to organ failure and death.
The main cellular effectors of fibrosis are myofibroblasts, which produce a collagen-rich ECM. In response to tissue injury, damaged cells and leukocytes produce pro-fibrotic factors such as TGFβ, IL-13 and PDGF, which activate fibroblasts to αSMA-expressing myofibroblasts, and recruit myofibroblasts to the site of injury. Myofibroblasts produce a large amount of ECM, and are important mediators in aiding contracture and closure of the wound. However, under conditions of persistent infection or during chronic inflammation there can be overactivation and recruitment of myofibroblasts, and thus over-production of ECM components, resulting in the formation of excess fibrous connective tissue.
Inflammatory reactions play an important part in triggering fibrosis in many different organ systems. Inflammation can lead to excess in deposition of ECM components in the affected tissues. Low-grade but persistent inflammation is also thought to contribute to the progression of fibrosis in cardiovascular disease and hypertension. In many fibrotic disorders, a persistent inflammatory trigger is crucial to upregulation of production of growth factors, proteolytic enzymes, angiogenic factors and fibrogenic cytokines, which stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture.
In some embodiments fibrosis may be triggered by pathological conditions, e.g. conditions, infections or disease states that lead to production of pro-fibrotic factors such as TGFβ1. In some embodiments, fibrosis may be caused by physical injury/stimuli, chemical injury/stimuli or environmental injury/stimuli. Physical injury/stimuli may occur during surgery, e.g. iatrogenic causes. Chemical injury/stimuli may include drug induced fibrosis, e.g. following chronic administration of drugs such as bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin (Daba et al., Saudi Med J 2004 June, 25(6): 700-6). Environmental injury/stimuli may include exposure to asbestos fibres or silica.
Fibrosis can be of any tissue/organ of the body. In some embodiments, fibrosis is of the heart, kidney, liver, lung, skeletal muscle, blood vessels, eye, skin, pancreas, bowel, small intestine, large intestine, colon, brain, or bone marrow. In some embodiments, the fibrosis is of the liver. In some embodiments, the fibrosis is of the heart, lung or kidney. Fibrosis may also occur in multiple tissues/organs at once.
Thus, the present invention provides methods and articles (agents and compositions) for the treatment and/or prevention of diseases characterised by fibrosis through inhibition of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Thus, in one aspect the present invention provides a method of treating or preventing a disease characterised by fibrosis, comprising inhibiting at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Also provided is a method of treating or preventing a disease characterised by fibrosis, comprising administering a therapeutically or prophylactically effective amount of an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to a subject. The method may comprise administering two or more (i.e. 2, 3, 4, 5, 6, 7, 8 or 9) inhibitors that target two or more (i.e. 2, 3, 4, 5, 6, 7, 8 or 9) of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Also provided is an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB for use in a method of treating or preventing a disease characterised by fibrosis.
Also provided is the use of an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in the manufacture of a medicament for use in a method of treating or preventing a disease characterised by fibrosis.
A “disease characterised by fibrosis” refers to a disease in which fibrosis and/or profibrotic processes are pathologically implicated. A “disease characterised by fibrosis” may be fibrosis, e.g. of any cell, tissue or organ.
Diseases characterised by fibrosis include but are not limited to: respiratory conditions such as pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, obliterative bronchiolitis, Hermansky-Pudlak syndrome, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, tumor stroma in lung disease, and asthma; chronic liver disease, cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), schistosomal liver disease, cardiovascular conditions such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), fibrosis of the atrium, atrial fibrillation, fibrosis of the ventricle, ventricular fibrillation, myocardial fibrosis, Brugada syndrome, myocarditis, endomyocardial fibrosis, myocardial infarction, fibrotic vascular disease, hypertensive heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), tubulointerstitial and glomerular fibrosis, atherosclerosis, varicose veins, cerebral infarcts; neurological conditions such as gliosis and Alzheimer's disease; muscular dystrophy such as Duchenne muscular dystrophy (DMD) or Becker's muscular dystrophy (BMD); gastrointestinal conditions such as Crohn's disease, microscopic colitis and primary sclerosing cholangitis (PSC); skin conditions such as scleroderma, nephrogenic systemic fibrosis and cutis keloid; arthrofibrosis; Dupuytren's contracture; mediastinal fibrosis; retroperitoneal fibrosis; myelofibrosis; Peyronie's disease; adhesive capsulitis; kidney disease (e.g., renal fibrosis, nephritic syndrome, Alport's syndrome, HIV associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus); progressive systemic sclerosis (PSS); chronic graft versus host disease; diseases of the eye such as Grave's opthalmopathy, epiretinal fibrosis, retinal fibrosis, subretinal fibrosis (e.g. associated with macular degeneration (e.g. wet age-related macular degeneration (AMD)), diabetic retinopathy, glaucoma, corneal fibrosis, post-surgical fibrosis (e.g. of the posterior capsule following cataract surgery, or of the bleb following trabeculectomy for glaucoma), conjunctival fibrosis, subconjunctival fibrosis; arthritis; fibrotic pre-neoplastic and fibrotic neoplastic disease; and fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation/cancer radiotherapy).
It will be appreciated that many of the diseases/conditions recited in the preceding paragraph are interrelated. For example, fibrosis of the ventricle may occur post myocardial infarction, and is associated with DCM, HCM and myocarditis.
Fibrosis can lead directly or indirectly to, and/or increase susceptibility to development of, diseases. For example, more than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers (Affo et al. 2016, Annu Rev Pathol.), suggesting an important role for liver fibrosis in the premalignant environment (PME) of the liver.
Accordingly, the present invention also finds use in methods for the treatment and prevention of diseases associated with fibrosis, and/or for which fibrosis is a risk factor. In some embodiments, the disease associated with fibrosis, or for which fibrosis is a risk factor, is a cancer, e.g. cancer of the liver (e.g. hepatocellular carcinoma).
In some embodiments, the fibrosis to be treated/prevented according to the present invention may be of fibrosis that is associated with an upregulation of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB expression and/or activity, e.g. in cells/tissue/an organ in which the fibrosis occurs or may occur.
The therapy may be effective to inhibit development (delay/prevent) of the fibrosis, or of progression (e.g. worsening) of the fibrosis. In some embodiments therapy may lead to an improvement in the disease, e.g. a reduction in the symptoms of fibrosis. Prevention of fibrosis may refer to prevention of a worsening of the condition or prevention of the development of fibrosis, e.g. preventing an early stage fibrosis (e.g. inflammation, steatosis, NAFLD) developing to a later stage (e.g. fibrosis, cirrhosis, HCC).
Aspects of the present invention are concerned with the treatment/prevention of diseases in which proinflammatory processes are pathologically implicated. Inflammation is reviewed e.g. in Chen et al., Oncotarget. (2018) 9(6): 7204-7218, which is hereby incorporated by reference in its entirety. Inflammation refers to the bodily response to cellular/tissue injury, and is characterised by edema, erythema (redness), heat, pain, and loss of function (stiffness and immobility) resulting from local immune, vascular and inflammatory cell responses to infection or injury. The injury may result from e.g. of physical (e.g. mechanical) or chemical insult, trauma, infection, cancer or overactive/aberrant immune responses (e.g. autoimmune disease). Inflammation forms part of the innate immune response, and plays an important physiological role in wound healing and the control of infection, and contributes to the restoration of tissue homeostasis.
However, many diseases are associated with an overactive inflammatory response (i.e. excessive inflammation and/or aberrantly activated inflammation), and/or chronic (prolonged) inflammation. Herein, excessive and/or chronic inflammation may be referred to as “pathological inflammation”. Pathological inflammation may refer to inflammation which is implicated in (i.e. which positively contributes to) the pathology of a disease.
In some embodiments, the disease to be treated/prevented in accordance with the present invention is a disease characterised by chronic inflammation. In some embodiments, the disease to be treated/prevented is a disease characterised by an overactive inflammatory response.
In some embodiments, the treatment/prevention of chronic inflammation or an overactive inflammatory immune response associated with a chronic infection, cancer, autoimmune disease, degenerative disease or allergic disease is contemplated.
Pathological inflammation which is “associated with” a given disease (e.g. a chronic infection, a cancer, an autoimmune disease, a degenerative disease or an allergic disease) may refer to pathological inflammation caused by, initiated by and/or which is a consequence of the disease. Pathological inflammation associated with a given disease may be concurrent with the disease.
Chronic inflammation generally refers to inflammation lasting for prolonged periods of time, e.g. from months to years. Chronic inflammation can result e.g. from failure to properly control/eliminate an infectious agent causing inflammation (i.e. chronic infection), prolonged/repeated exposure to physical/chemical insult, prolonged/repeated exposure to an allergen (allergy), and autoimmune disease.
The chronic inflammation, overactive inflammatory immune response, chronic infection, cancer, autoimmune disease, degenerative disease or allergic disease may affect any tissue/organ of the body, e.g. the heart, kidney, liver, lung, skeletal muscle, blood vessels, eye, skin, pancreas, bowel, small intestine, large intestine, colon, brain, or bone marrow, or multiple tissues/organs at once.
An overactive inflammatory immune response generally refers to an inflammatory immune response that is excessive, and/or which has been activated inappropriately (i.e. an inflammatory immune response which is aberrant). An excessive inflammatory immune response refers to an inflammatory immune response which is greater than the response required for restoration of tissue homeostasis following injury to tissue (e.g. as a result of physical or chemical insult or infection). Aberrant inflammatory immune responses include inflammatory immune responses resulting from autoimmunity and allergy.
Chronic infections include persistent/unresolved infection by any infectious agent, e.g. chronic viral, bacterial, fungal and protozoal infections. Chronic viral infections may be caused e.g. by infection with human immunodeficiency viruses (HIVs), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr Virus (EBV), measles virus (MV), cytomegalovirus (CMV), human T-cell leukemia viruses (HTLVs), human herpesviruses (HHVs), herpes simplex viruses (HSVs), Varicella-Zoster virus (VZV), human papovaviruses (e.g. JC virus, BK virus), adenoviruses (AdVs), paroviruses or human papillomaviruses (HPVs). Chronic bacterial infections may be caused e.g. by infection with Mycobacterium tuberculosis Helicobacter pylori, Salmonella Typhi, Treponema pallidum, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Hemophilus influenza or Mycobacterium leprae. Chronic fungal infections may be caused e.g. by infection with Candida spp or Aspergillus. Chronic protozoal infections may be caused e.g. by infection with Plasmodium spp., Babesia spp., Giardia spp., Leishmania spp., Trypanosoma spp. or Toxoplasma spp.
A cancer may be any cancer. As used herein, cancers include any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumor. The cancer may be benign or malignant and may be primary or secondary (metastatic). A neoplasm or tumor may be any abnormal growth or proliferation of cells and may be located in any tissue. The cancer may be of tissues/cells derived from e.g. the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain) cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g. renal epithelia), gallbladder, oesophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal glad, larynx, liver, lung, lymph, lymph node, lymphoblast, maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissues, spleen, stomach, testis, thymus, thyroid gland, tongue, tonsil, trachea, uterus, vulva, and/or white blood cells.
An autoimmune disease may be selected from: diabetes mellitus type 1, diabetes mellitus type 2, coeliac disease, Graves' disease, inflammatory bowel disease (e.g. Crohn's disease), multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
Degenerative diseases are characterised by deterioration of cell/tissue/organ condition or function over time. Proinflammatory and profibrotic processes are implicated in the pathology of many degenerative diseases.
Degenerative disease include e.g. Alzheimer's disease, amyotrophic lateral sclerosis, cancers, Charcot-Marie-Tooth disease, chronic traumatic encephalopathy, cystic fibrosis, degenerative Leigh syndrome, Ehlers-Danlos syndrome, fibrodysplasia ossificans progressiva, Friedreich's ataxia, frontotemporal dementia, cardiovascular diseases (e.g. atherosclerotic cardiovascular disease (e.g. coronary artery disease, aortic stenosis), myocardial infarction, pulmonary arterial hypertension), Huntington's disease, infantile neuroaxonal dystrophy, keratoconus, keratoglobus, leukodystrophies, macular degeneration, Marfan's syndrome, mitochondrial myopathies, mitochondrial DNA depletion syndrome, multiple sclerosis, multiple system atrophy, muscular dystrophies, neuronal ceroid lipofuscinosis, Niemann-Pick disease, osteoarthritis, osteoporosis, Parkinson's disease, pulmonary arterial hypertension, all prion diseases (Creutzfeldt-Jakob disease, fatal familial insomnia etc.), progressive supranuclear palsy, retinitis pigmentosa, rheumatoid arthritis, Sandhoff Disease, spinal muscular atrophy, subacute sclerosing panencephalitis, Tay-Sachs disease and vascular dementia.
An allergic disease may be selected from allergic asthma, allergic rhinitis, food allergy and atopic dermatitis.
In some embodiments the chronic inflammation, overactive inflammatory immune response, chronic infection, cancer, autoimmune disease or allergic disease may be of: an organ of the cardiovascular system, e.g. of the heart or blood vessels; an organ of the gastrointestinal system, e.g. of the liver, bowel, small intestine, large intestine, colon, or pancreas; an organ of the respiratory system, e.g. the lung; the skin; an organ of the nervous system, e.g. the brain; an organ of the urinary system, e.g. the kidneys; or an organ of the musculoskeletal system, e.g. muscle tissue.
Pathological inflammation often leads to fibrosis—see e.g. Mack, Matrix Biol. (2018) 68-69:106-121 and Suthahar et al., Curr Heart Fail Rep. (2017) 14(4): 235-250, both of which are hereby incorporated by reference in their entirety.
The present invention also finds use in methods for the treatment and prevention of diseases associated with pathological inflammation, and/or for which pathological inflammation is a risk factor. In some embodiments, the disease associated with pathological inflammation, or for which pathological inflammation is a risk factor, is fibrosis or a disease characterised by fibrosis.
In some embodiments, the pathological inflammation to be treated/prevented according to the present invention may be of pathological inflammation that is associated with an upregulation of expression and/or activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, e.g. in cells/tissue/an organ in which the pathological inflammation occurs or may occur.
The therapy may be effective to inhibit development (delay/prevent) of the pathological inflammation, or of progression (e.g. worsening) of the pathological inflammation. In some embodiments therapy may lead to an improvement in the disease, e.g. a reduction in the symptoms of pathological inflammation. Prevention of pathological inflammation may refer to prevention of a worsening of the condition or prevention of the development of pathological inflammation, e.g. preventing an early stage pathological inflammation developing to a later stage.
Therapeutic/prophylactic intervention in accordance with the present invention may be employed in the context of additional treatment for the relevant disease. That is, expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may be inhibited in a subject (e.g. by treatment with a suitable inhibitor such as those described herein) that is also receiving/has received/will receive further therapeutic/prophylactic intervention for the treatment/prevention of the disease.
The experimental examples show that proliferation, expansion and regeneration of liver and lung cells/tissue can be achieved via inhibition of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In accordance with various aspects of the present invention, a method of treating and/or preventing a disease according to the present invention may comprise one or more of the following:

- Reducing the level of gene/protein expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reducing the level of activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB;
- Reducing the level of a correlate of fibrosis (e.g. a collagen, αSMA, periostin, fibronectin, CTGF, vimentin or lumican);
- Reducing gene/protein expression of a pro-fibrotic factor (e.g. a collagen, αSMA, periostin,
- fibronectin, CTGF, vimentin or lumican);
- Reducing the number/proportion of myofibroblasts;
- Reducing the level of a correlate of pathological inflammation;
- Reducing gene/protein expression of a pro-inflammatory factor;
- Reducing the number/proportion of myofibroblasts;
- Increasing the function of an organ/tissue affected by the disease;
- Stimulating/increasing proliferation of a cell affected by the disease;
- Stimulating/increasing expansion of a cell affected by the disease;
- Stimulating/increasing regeneration of a cell affected by the disease;
- Stimulating/increasing proliferation of a myoblast;
- Stimulating/increasing expansion of a myoblast;
- Stimulating/increasing regeneration of a myoblast;
- Increasing the number/proportion of health myoblasts;
- Stimulating/increasing regeneration of an organ/tissue affected by the disease;
- Stimulating/increasing proliferation and/or expansion of a cell in an organ/tissue affected by the disease;
- Stimulating/increasing proliferation and/or expansion of a hepatocyte, e.g. that is affected by the disease or that is in an organ/tissue affected by the disease;
- Stimulating/increasing regeneration of liver tissue;
- Stimulating/increasing regeneration of lung tissue;
- Stimulating/increasing regeneration of the liver;
- Stimulating/increasing regeneration of the lung;
- Increasing function of an organ/tissue affected by the disease;
- Increasing liver function;
- Increasing lung function;
- Increasing wound healing in an organ/tissue affected by the disease;
- Increasing wound healing in liver tissue;
- Increasing wound healing in lung tissue;
- Protecting an organ/tissue affected by the disease;
- Protecting a liver/liver tissue affected by the disease;
- Protecting a lung/lung tissue affected by the disease;
- Increasing the survival of a subject having the disease;
- Reducing the number/proportion of macrophages in an organ/tissue affected by the disease; and/or
- Reducing the number/proportion of monocytes in an organ/tissue affected by the disease;

Methods for Treating a Subject are Provided Herein.
The disclosure teaches a method of treating a condition or disease in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to treat the condition or disease in the subject.
Disclosed herein is a method of treating a liver condition or disease in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to treat the liver condition or disease in the subject.
A “gene associated with organ regeneration” as used herein may refer to one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB genes. A “corresponding gene product associated with organ regeneration” as used herein may refer to an mRNA encoded by one or more genes above, or a MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB protein.
In one embodiment, a subject herein is suffering from a liver condition or disease, as described herein. The methods described herein may comprise preventing or treating the liver condition or disease.
In one embodiment, a subject herein is suffering from a lung condition or disease. The lung condition or disease may be a cigarette or viral-induced lung condition or disease. The lung condition or disease may be lung damage or fibrosis. The method may comprise preventing or treating the lung condition or disease.
Disclosed herein is a method of protecting a subject from liver damage or a disease associated with fibrosis, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to protect the subject from liver damage. The inhibitor may be one described herein. A gene/corresponding gene product associated with organ regeneration may be one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Disclosed herein is an inhibitor of a gene or corresponding gene product associated with organ regeneration for use in preventing or treating a liver condition or disease in the subject. In one embodiment, the inhibitor is capable of stimulating or increasing proliferation of hepatocytes in the subject.
Disclosed herein is the use of an inhibitor of a gene or corresponding gene product associated with organ regeneration in the manufacture of a medicament for preventing or treating a liver condition or disease in the subject.
Disclosed herein is a method of enhancing cell function in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell function in the subject. “Enhancing cell function” refers to improving the endogenous activity of a cell, e.g. signalling, proliferation, expansion. Function of a cell may be enhanced starting from a healthy state, or from a diseased/impaired state.
The method may comprise improving the robustness of the cell under diseased condition. The term robustness refers to being able to survive under diseased condition.
Disclosed herein is a method of enhancing cell viability in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell viability in the subject, e.g. in inhibitor described herein.
The present disclosure teaches a method of stimulating or increasing proliferation and/or regeneration of a cell in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to stimulate or increase proliferation of the cell in the subject.
In one embodiment, the method further increases the robustness of the cell under diseased conditions in the subject.
In one embodiment, the gene associated with organ regeneration is identified by knocking down the gene in a hepatocyte of an animal model and detecting proliferation and/or regeneration of the hepatocyte in the animal model.
The gene associated with organ regeneration is selected from the group consisting of Microfibril Associated Protein 4 (Mfap4), Glyoxylate and Hydroxypyruvate Reductase (Grhpr), Integrin Alpha FG-GAP Repeat Containing 1 (Itfg1), ATP binding cassette subfamily C member 4 (ABCC4), p21 (RAC1) activated kinase 3 (PAK3), TMF1 regulated nuclear protein 1 (TRNP1), Apelin (APLN), Kindesin Family Member 20A (KIF20A) and Lymphotoxin beta (LTB).
A “gene product” is a biopolymeric product that is expressed or produced by a gene. A gene product may be, for example, an unspliced RNA, an mRNA, a splice variant mRNA, a polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide etc. Also encompassed by this term is biopolymeric products that are made using an RNA gene product as a template (i.e. cDNA of the RNA). A gene product may be made enzymatically, recombinantly, chemically, or within a cell to which the gene is native. In many embodiments, if the gene product is proteinaceous, it exhibits a biological activity. In many embodiments, if the gene product is a nucleic acid, it can be translated into a proteinaceous gene product that exhibits a biological activity.
Disclosed herein is an in vitro or in vivo method for reducing gene and/or protein expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell, comprising introducing an inhibitor described herein into the cell. In some embodiments, the inhibitor is an inhibitory nucleic acid as described herein.
Disclosed herein is a method of regenerating liver tissue in vitro or in vivo, the method comprising inhibiting at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell of the tissue, e.g. using an inhibitor described herein.
Disclosed herein is a method for preventing age-dependent decline in the regenerative capacity of a hepatocyte, the method comprising inhibiting at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell of the tissue, e.g. using an inhibitor described herein.
The term “treating” as used herein may refer to (1) preventing or delaying the appearance of one or more symptoms of the disorder; (2) inhibiting the development of the disorder or one or more symptoms of the disorder; (3) relieving the disorder, i.e., causing regression of the disorder or at least one or more symptoms of the disorder; and/or (4) causing a decrease in the severity of one or more symptoms of the disorder. The term “treating” may refer to regeneration of the tissue/organ in question, or preventing a disease/condition from progressing to a later, more severe stage.
The term “administering” refers to contacting, applying, injecting, transfusing or providing an inhibitor as referred to herein to a subject.
The term “subject” as used throughout the specification is to be understood to mean a human or may be a domestic or companion animal. While it is particularly contemplated that the methods of the invention are for treatment of humans, they are also applicable to veterinary treatments, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates. The “subject” may include a person, a patient or individual, and may be of any age or gender.
The patient may have a disease described herein. A subject may have been diagnosed with a disease requiring treatment, may be suspected of having such a disease, or may be at risk from developing a disease.
In embodiments according to the present invention the subject is preferably a human subject. In embodiments according to the present invention, a subject may be selected for treatment according to the methods based on characterisation for certain markers of a disease described herein.
In some embodiments, any method disclosed herein comprises administering an inhibitor according to the present disclosure into a subject, organ, tissue or cell. The organ, tissue or cell may be in vivo or in vitro. Any method described herein may be performed in vivo or in vitro.
Aspects and embodiments of the present invention concern detection of expression of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (gene and/or protein expression) and/or activity in a cell/tissue/organ of a subject, e.g. as determined by analysis of a cell/tissue/organ of a subject, e.g. in a sample obtained from the subject (such as an in vitro cell/tissue/organ/sample).
Disclosed herein is a method of detecting a liver condition or disease in a subject, the method comprising detecting in a sample the level of one or more biomarkers associated with liver regeneration, wherein a change in the level of the one or more biomarkers as compared to a reference indicates that the subject is suffering from a liver condition or disease. The one or more biomarkers may be one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
Upregulated expression and/or activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may identify a subject as a subject to be treated with an inhibitor of at least one of those genes/proteins in accordance with the present invention.
Upregulated expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB refers to a level of expression/activity that is greater than would be expected for a cell/tissue of a given type. Gene or protein expression and activity can be analysed as described herein.
Upregulation may be determined by measuring the level of expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a cell/tissue. Comparison may be made between the level of expression/activity in a cell or tissue sample from a subject and a reference level of expression/activity, e.g. a value/range of values representing a normal level of expression/activity for the same or corresponding cell/tissue type. In some embodiments reference levels may be determined by detecting expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB in a control sample, e.g. in corresponding cells or tissue from a healthy subject or from healthy tissue of the same subject. In some embodiments reference levels may be obtained from a standard curve or data set.
A sample obtained from a subject may be of any kind. A biological sample may be taken from any tissue or bodily fluid, e.g. a blood sample, blood-derived sample, serum sample, lymph sample, semen sample, saliva sample, synovial fluid sample. A blood-derived sample may be a selected fraction of a patient's blood, e.g. a selected cell-containing fraction or a plasma or serum fraction. A sample may comprise a tissue sample or biopsy; or cells isolated from a subject. Samples may be collected by known techniques, such as biopsy or needle aspirate. Samples may be stored and/or processed for subsequent determination of the level of expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
In some preferred embodiments a sample may be a tissue sample, e.g. biopsy, taken from a tissue/organ affected by a disease described herein. A sample may contain cells.
A subject may be selected for therapy/prophylaxis in accordance with the present invention based on determination that the subject has an upregulated level of expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB. Upregulated expression/activity of said genes/proteins may serve as a marker of a disease suitable for treatment in accordance with the present invention.
Following selection, a subject may be treated to inhibit expression and/or activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, e.g. by administration of an inhibitor of at least one of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. that has an upregulated level of expression/activity).
Detection of upregulation of expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may also be used in a method of diagnosing a disease described herein, identifying a subject at risk of developing a disease described herein, and in methods of prognosing a subject's response to inhibition of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB (e.g. via treatment with an inhibitor targeting one or more of said genes/proteins).
In some embodiments a subject may be suspected of having or suffering from a disease, e.g. based on the presence of other symptoms indicative of the disease in the subject's body or in selected cells/tissues of the subject's body, or be considered at risk of developing the disease, e.g. because of genetic predisposition or exposure to environmental conditions, known to be risk factors for the disease. Determination of upregulation of expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB may confirm a diagnosis or suspected diagnosis, or may confirm that the subject is at risk of developing the disease. The determination may also diagnose a disease or predisposition as one suitable for treatment with an inhibitor of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
As such, a method of providing a prognosis for a subject having, or suspected of having a disease may be provided, the method comprising determining whether expression/activity of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB is upregulated in a sample obtained from the subject and, based on the determination, providing a prognosis for treatment of the subject with a inhibitor of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB.
The method may further comprise the step of selecting the subject for treatment with an inhibitor of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB, and/or administering an inhibitor of one or more of MFAP4, GRHPR, ITFG1, ABCC4, PAK3, TRNP1, APLN, KIF20A, and/or LTB to the subject in order to provide a treatment for a disease described herein in the subject or to prevent development or progression of a disease described herein in the subject.
Methods of diagnosis or prognosis may be performed in vitro on a sample obtained from a subject, or following processing of a sample obtained from a subject. Once the sample is collected, the patient is not required to be present for the in vitro method of diagnosis or prognosis to be performed and therefore the method may be one which is not practised on the human or animal body. The sample obtained from a subject may be of any kind, as described herein above.
Other diagnostic or prognostic tests may be used in conjunction with those described here to enhance the accuracy of the diagnosis or prognosis or to confirm a result obtained using the tests described herein.
The terms “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount of a compound that is sufficient to effect treatment as defined below, when administered to a patient (e.g., a human) in need of such treatment in one or more doses. The therapeutically effective amount will vary depending upon the patient, the disease being treated, the weight and/or age of the patient, the severity of the disease, the nature of the agent, or the manner of administration as determined by a qualified prescriber or care giver. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.
Multiple doses of the agent may be provided. One or more, or each, of the doses may be accompanied by simultaneous or sequential administration of another therapeutic agent.
Multiple doses may be separated by a predetermined time interval, which may be selected to be one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. By way of example, doses may be given once every 7, 14, 21 or 28 days (plus or minus 3, 2, or 1 days).
In therapeutic applications, inhibitors for use as described herein are preferably formulated as a medicament or pharmaceutical together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
As used herein, “pharmaceutically acceptable carrier” includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are not deleterious to the disclosed compound or use thereof. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.). Each carrier, adjuvant, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, adjuvants, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
The formulations may be prepared for topical, parenteral, systemic, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intra-conjunctival, subcutaneous, oral or transdermal routes of administration which may include injection. Injectable formulations may comprise the selected agent in a sterile or isotonic medium. The formulation and mode of administration may be selected according to the agent and disease to be treated/prevented.
Disclosed herein is a method of screening for an inhibitor of a gene or corresponding gene product associated with organ regeneration by: a) contacting the gene or corresponding gene product with a chemical compound library, and b) identifying a chemical compound within the library that is binds to the gene or corresponding gene product to inhibit the expression or function of the gene or corresponding gene product.
Also provided herein are reporter cells lines for screening of small compound inhibitors for a gene or corresponding gene product associated with cell regeneration.
Numbered Paragraphs
1. A method of stimulating or increasing proliferation and/or regeneration of a cell in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to stimulate or increase proliferation of the cell in the subject.
2. The method of paragraph 1, wherein the method increases the robustness of the cell under diseased conditions in the subject.
3. The method of paragraph 1, wherein the gene associated with organ regeneration is identified by knocking down the gene in a hepatocyte of an animal model and detecting proliferation and/or regeneration of the hepatocyte in the animal model.
4. The method of paragraph 2, wherein the gene associated with organ regeneration is selected from the group consisting of Microfibril Associated Protein 4 (Mfap4), Glyoxylate and Hydroxypyruvate Reductase (Grhpr), Integrin Alpha FG-GAP Repeat Containing 1 (Itfg1), ATP binding cassette subfamily C member 4 (ABCC4), p21 (RAC1) activated kinase 3 (PAK3), TMF1 regulated nuclear protein 1 (TRNP1), Apelin (APLN), Kindesin Family Member 20A (KIF20A) and Lymphotoxin beta (LTB).
5. The method of paragraph 1, wherein the inhibitor is a nucleic acid, peptide, antibody or small molecule inhibitor.
6. The method of paragraph 5, wherein the inhibitor is a nucleic acid inhibitor comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in any of Tables 1-14 or an RNAi agent that hybridizes to the complement of an RNA sequence listed in any of Tables 1-14 under stringency conditions.
7. The method of paragraph 1, wherein the subject is suffering from a liver condition or disease.
8. The method of paragraph 7, wherein the liver condition or disease is selected from the group consisting of acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), hepatitis and liver damage.
9. The method of paragraph 7, wherein the method comprises preventing or treating the liver condition or disease.
10. A method of enhancing cell function in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell function in the subject.
11. The method of paragraph 10, wherein the method comprises improving the robustness of the cell under diseased condition.
12. A method of enhancing cell viability in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to enhance cell viability in the subject.
13. A method of treating a liver condition or disease in a subject, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to treat the liver condition or disease in the subject.
14. A method of protecting a subject from liver damage, the method comprising administering to the subject an inhibitor of a gene or corresponding gene product associated with organ regeneration for a sufficient time and under conditions to protect the subject from liver damage.
15. A method of detecting a liver condition or disease in a subject, the method comprising detecting in a sample the level of one or more biomarkers associated with liver regeneration, wherein a change in the level of the one or more biomarkers as compared to a reference indicates that the subject is suffering from a liver condition or disease.
16. An inhibitor of a gene or corresponding gene product associated with organ regeneration for use in preventing or treating a liver condition or disease in the subject.
17. The inhibitor of paragraph 16, wherein the liver condition or disease is selected from the group consisting of acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC) hepatitis or liver damage.
18. The inhibitor of paragraph 17, wherein the inhibitor is capable of stimulating or increasing proliferation of hepatocytes in the subject.
19. Use of an inhibitor of a gene or corresponding gene product associated with organ regeneration in the manufacture of a medicament for preventing or treating a liver condition or disease in the subject.
20. The use of paragraph 19, wherein the liver condition or disease is selected from the group consisting of acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC) hepatitis or liver damage.
21. The use of paragraph 19, wherein the inhibitor is capable of stimulating or increasing proliferation of hepatocytes in the subject.
22. A nucleic acid inhibitor consisting, comprising or encoding an RNAi agent having at least 70%, 80%, 90% or 95% sequence identity to an RNA sequence listed in any of Tables 1-14 or an RNAi agent that hybridizes to the complement of an RNA sequence listed in any of Tables 1-14 under stringency conditions.
23. A method of screening for an inhibitor of a gene or corresponding gene product associated with organ regeneration by: a) contacting the gene or corresponding gene product with a chemical compound library, and b) identifying a chemical compound within the library that is binds to the gene or corresponding gene product to inhibit the expression or function of the gene or corresponding gene product.
The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.
Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
As used in this application, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an agent” includes a plurality of agents, including mixtures thereof. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/−10%.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
Certain embodiments of the invention will now be described with reference to the following figures and examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.
For standard molecular biology techniques, see Sambrook, J., Russel, D. W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001, Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, which is hereby incorporated by reference in its entirety.

SUMMARY OF THE FIGURES

Embodiments and experiments illustrating the principles of the invention will now be discussed, by way of non-limiting example only, with reference to the accompanying figures in which:

FIG. 1A, 1B, 1C, 1D. Functional genetic in vivo RNAi screen for modulators of liver regeneration FIG. 1A) Outline of screen. A library of 250 shRNAs targeting 89 genes was delivered to the liver by hydrodynamic-tail vine injection (HDTV) of the transposon based construct (upper panel) in combination with a sleeping beauty 13 (SB13) encoding plasmid (5 independent mice). After stable integration in ˜5 to 10% of hepatocytes, thioacetamide (TAA) treatment (3 times per week for 8 weeks) induces chronic liver damage associated with advanced liver fibrosis. Changes in shRNA abundance is detected by deep sequencing. FIG. 1B) Representation of fold change for each shRNA. The majority of shRNAs is depleted but a small number is clearly enriched. FIG. 1C) ROMAampl-library (250 shRNAs) distribution. Abundance of potential candidates is shown. Heatmap based representation of enrichment (dark grey) or depletion (light grey) for each animal. Upper panel shows all shRNAs (each raw represents one animal). Lower panel represents a higher magnification for highly significant enriched, depleted and neutral shRNAs (each column represents one animal). FIG. 1D) Functional genetic screen identifies high confidence candidates (zoom in of FIG. 1 B) is shown). At least two independent shRNAs were enriched targeting Mfap4, Grhpr, and Itfg1. Furthermore, non-targeting control (shNC) shRNAs (Renilla.713 and Luciferase.1309) did not show significant enrichment or depletion and known important liver regeneration genes are depleted, whereas shRNAs targeting the c-Met an essential receptor for liver regeneration are depleted. These results give confidence in the screening approach.

FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G: In vitro validation of targeting Mfap4 for enhancing regeneration—shRNA mediated knockdown of Mfap4 accelerates proliferation rate in embryonic liver cell line FIG. 2A) Test of knockdown efficiency of top scoring shRNAs targeting Mfap4. Upper panel, retroviral backbone for generating stable cell lines. Lower panel, Western blot showing efficient knockdown of Mfap4 by our shRNAs (control: aTub=α-TUBULIN). FIG. 2B) Schematic outline for stable cell line based assays. FIG. 2C) Wound healing assay in TIB 73 (BNLCL.2) cell line. Stable cell lines were grown to full confluence, then the silicon gasket was removed leaving a defined cell free area. Filling of this “wound” gap was monitored. In the left panels representative images for each group are shown. Three technical replicates were performed. On the right panel the quantification over different time points is shown (Data was analyzed by ImageJ software and 2-way ANOVA test of GraphPad Prism software). Significant difference between shMfap4.1356 (SEQ ID NO: 1), shMfap4.760 (SEQ ID NO: 2) and shNC is shown by ‘*’). FIG. 2D) EdU incorporation assay. DNA synthesis of TIB 73 cells (BNLCL.2) transfected with shMfap4.1356 (SEQ ID NO: 2) and shNC was assessed by EdU assays. Quantification shows significant difference between experiment and control. Three technical replicates were performed. FIG. 2E) Cell doubling. Doubling time assay results are shown. Cells were seeded at same seeding densities. Doubling time was calculated based on the exponential phase of the growth curve. Three technical replicates were performed. FIG. 2F) Cell cycle analysis by flow cytometry using the Guava Muse Cell Analyzer. Shown is the percentage of cells in the indicated cell cycle phase. Greater amount of cells in G2 phase is indicated in case of experiment (cells with stable Mfap4 knockdown by shMfap4.1356 and shMfap4.760) compared to control NC. FIG. 2G) Wound healing assay using adult liver mouse cell line AML12. Left panel, the same effects were observed as in FIG. 2C). Right panel. quantification of FIG. 2A) shows significantly faster wound closure already at the 14 h time-point.

FIG. 3A, 3B, 3C, 3D, 3E, 3F: Mfap4 knockdown accelerates liver repopulation FIG. 3A) FAH knockout mice based liver repopulation assay. Upper panel shows the outline of the transposon based vector for the expression of the enzyme FAH, the marker GFP and the shRNA of interest. Lower panel shows the outline and rational for the assay. If the knockdown of a certain shRNA is able to enhance regeneration and accelerate hepatocyte proliferation, we should be able to see a faster clonal expansion compared to a control shRNA starting from the stably integrated hepatocytes. FIG. 3B) GFP imager images. GFP imaging of explanted mouse livers shows enhanced clonal expansion (repopulation) of hepatocytes stably expressing shMfap4.1356 (SEQ ID NO: 1) compared to hepatocytes expressing shNC (day 18 after HDTV injection of 25 μg of the indicated plasmid). Representative photographs are shown for each group (n=8 in group with shMfap4.1356, n=6 in group with shMfap4.760, n=6 in group with shNC). Light, white points represent GFP positive macroscopically visible clonal expansions. FIG. 3C) Native GFP on tissue sections. Shown are representative GFP fluorescence photographs of liver sections (200×) of FAH−/− mice 18 days after in vivo delivery of transposon constructs either expressing shMfap4 or a control shRNA corresponding to B). FIG. 3D) Histological analysis (immunostaining against GFP) for GFP-positive cells of mouse livers with stable expression of shMfap4.1356 (SEQ ID NO: 1), shMfap4.760 (SEQ ID NO: 2) and shNC (shown are representative photographs, n=8 in group with shMfap4.1356, n=6 in group with shMfap4.760, n=6 in group with shNC). Day 18 after HDTV injection of 1.25 μg of the indicated plasmid (200× magnification). Increased clonal expansion can be seen for shMfap4. FIG. 3E) Quantification of GFP-positive cells (corresponding to FIG. 3D) shows significant increase in GFP positive hepatocytes in case of Mfap4 knockdown compared to control. Each dot represents one animal. FIG. 3F) Kaplan-Meier survival curve of FAH−/− mice injected with a 1:30 (0.83 μg plasmid and 0.17 mg SB13) dilution of either p/T-FAHIG-shMfap4.1356 (n=5) or p/T-FAHIG-shNC (n=5) and SB13 (p<0.05). NTBC off indicates the time of NTBC drug removal, inducing the selection process (1 day post injection).

FIG. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H: “Western Diet” (WD) mouse fatty liver model FIG. 4A) WD+fructose Diet facts. The used diet is rich in fat and carbohydrates. 45% energy comes from fat, predominantly saturated fat, with 0.2% cholesterol. In addition, the animals get 60% fructose/water (wt/vol). FIG. 4B) Pathological evaluation. Histological slides of liver tissue form C56B16 mice exposed for the indicated time to the “Western Diet” or normal chow were evaluated and scored by a certified pathologist. Shown are the scoring results for steatosis and fibrosis. Each point represents an animal. FIG. 4C) Mice on “Western Diet” show a progressive weight gain independent of gender. FIG. 4D) WD model shows progressive fibrosis similar to human patients (see FIG. 4E). FIG. 4E) Progressive increase in fibrosis in human patients based and disease stage, similar to the mouse model (FIGS. 4D & 4B). FIG. 4F). Advanced liver fibrosis can already macroscopically be detected after 24 weeks of WD (representative image). FIG. 4G) After 24 weeks of WD mouse liver show high levels of steatosis (H&E stained liver tissue, representative image). FIG. 4H) Sirius Red staining for collagen fibers indicating advanced fibrosis after 24 weeks of WD exposure.

FIG. 5A, 5B, 5C, 5D, 5E, 5F: Mfap4 knockdown attenuates NASH related liver fibrosis FIG. 5A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months, so that every hepatocyte in the liver expresses the shRNA construct of interest. After full repopulation was reached mice were exposed to the “Western Diet” (high fat diet and 60% fructose) for 24 weeks. Livers were harvested, processed and analyzed. FIG. 5B) Representative macro-photographs of the livers are shown. Already macroscopically differences between groups were visible. FIG. 5C) Picro Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (n=5 per experimental group and n=7 per control group; representative sections are shown, 50× magnification). FIG. 5D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental group. Fibrosis score is significantly lower in the experimental group compared to the control group. FIG. 5E) The score of oval cell hyperplasia is shown. The score was given by a certified pathologist, who was blinded regarding the experimental group. The score is significantly lower (=0) in the experimental group compared to the control group. Oval cell hyperplasia is considered a compensatory mechanism, if regeneration through hepatocytes is not sufficient anymore. FIG. 5F) Representative GFP-scanner macro-photographs of the livers are shown. Strong GFP signal on the surface of the livers indicates full repopulation.

FIG. 6A, 6B, 6C, 6D: Mfap4 knockdown attenuates chronic liver damage related liver fibrosis FIG. 6A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that chronic liver damage was induced by repetitive doses of thioacetamide administered intraperitoneal 3 times per week for 8 weeks. Livers were harvested, processed and analyzed. FIG. 6B) Representative macro-photographs of the livers are shown. Already macroscopically differences between groups were visible. FIG. 6C) Picro Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (n=6 per experimental group and n=7 per control group; representative sections are shown, 50× magnification). FIG. 6D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental groups. Fibrosis score is significantly lower in the experimental group compared to the control group.

FIG. 7A, 7B, 7C, 7D, 7E, 7F, 7G, 7H, 7I, 7J: Mfap4 knockdown accelerates liver regeneration after partial hepatectomy (PH) FIG. 7A) Experimental outline. FRGN were injected with our constructs, then, mice were kept for full repopulation for 3 months. FRGN mice are FAH−/−, Rag2−/−, II2rg−/− on a NOD background and are immune compromised. After full repopulation of mouse liver, ⅔ of the liver was surgically removed. The remaining regenerating liver was harvested 48 h after surgery. FIG. 7B) Representative photographs of Ki67 immunofluorescence stained (top row) and DAB Ki67-stained (bottom row) liver sections 48 h post hepatectomy are shown (200× magnification, n=5 per experimental/control group). FIG. 7C) Quantification of Ki67 positive cells of DAB-stained liver sections (corresponding to FIG. 7B)) show increased hepatocyte proliferation after partial hepatectomy in shMfap4-expressing livers compared to shNC livers (individual points represent individual animals, data shows average±SEM, n=5 per group). FIG. 7D) Western blot analyses for cyclin A (nuclear extracts from repopulated mouse livers at the indicated time point) indicate an earlier cell-cycle entry and faster cell-cycle progression of shMfap4-expressing mouse livers (n=2). FIG. 7E) Experimental outline. Immune-competent FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that ⅔ of the liver was surgically removed. The remaining regenerating liver was harvested 42 h and 48 h after surgery. FIG. 7F) Representative photographs of DAB Ki67-stained liver sections 42 h (n=5 per experimental group, n=6 per control group) and 48 h (n=5 per experimental group, n=10 per control group) post hepatectomy are shown (200× magnification). FIG. 7G) Quantification of Ki67 positive cells of DAB-stained liver sections (corresponding to FIG. 7B)) show increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in shMfap4-expressing livers compared to shNC livers (individual points represent individual animals, data shows average±SEM). FIG. 7H) Western blot analyses for cyclin E (nuclear extracts from repopulated mouse livers at the indicated time point) indicate an earlier cell-cycle entry and faster cell-cycle progression of shMfap4-expressing mouse livers (n=2). FIG. 7I) GFP-imaging of fully repopulated FAH−/− livers (3 months post-HDTV injections) after ⅔ surgical partial removal of livers corresponding to different time-points of PHx. Strong GFP signal on the surface of the livers indicates full repopulation. FIG. 7J) Representative pictures of DAB GFP staining which show that full repopulation of FAH livers is around 90-95%. Dark brown zones represent repopulated hepatocytes, light brow zones are non-repopulated.

FIG. 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8J, 8K: In vivo knockdown of Mfap4 impacts mTOR and p38 signalling FIG. 8A) Schematic outline of experiment. Whole-cell protein extracts from repopulated mouse livers were isolated and analyzed by protein array. FIG. 8B) Heat map shows results for phospho-antibody MAPK pathway protein array. Whole-cell protein extracts from repopulated mouse livers with stable expression of either shMfap4 or shNC were analyzed (shown is the relative spot intensity). FIG. 8C) According to STRING database, all indicated proteins are interacting and are linked to cell growth and proliferation. FIG. 8D) After performing a broad protein array focused Western blot experiments were done. Results of Western blot are shown here. Proteins from fully repopulated livers were isolated. P-P70S6k, p-p38, p-mTOR, p-ERK2 are greater expressed in case of Mfap4 knockdown compare to control and, thus, show stronger activation in case of Mfap4 knockdown compared to control. There are 3 biological replicates in experiment and 3 biological replicates in control. FIG. 8E) Schematic representation for mTOR mediated regulation. The specific mTOR phosphorylation is upstream of p70S6k activation and leads to enforced translation. FIG. 8F Wound healing under double knockdown conditions. Based on pathway analysis double knockout experiments were commenced. Our stable cell line was expanded, cells were treated with respective siRNAs and the silicon gasket was removed. Wound healing was monitored. Slower growth and migration were observed in case of double-knockdown of Mfap4 and p70S6k and Mfap4 and p38. FIG. 8G) Western blot on proteins from cells in FIG. 8F were isolated. Interestingly p38 knockdown also affects p70S6k. FIG. 8H) Schematic outline of preparation of stable cell line with Mfap4 knockdown for transcriptomic analysis. FIG. 8I) Principal component analysis for AML12-shMfap4.1356, AML12-shMfap4.760, AML12-shNC, (Rb88-RMA050 & Ren_RMA061) and AML12 (AML_RMA052) is shown. We observed cluster separation between experiment and control. FIG. 8J) Heatmap of the following samples is shown. Ptgs2, Areg, Dhrs9, Hmox1, Nqo1 are upregulated in experimental samples compared to control and these genes are known to be involved in liver regeneration according to the literature. FIG. 8K) String Database shows connections between proteins which are upregulated according to FIGS. 8D and 8J.

FIG. 9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H, 9I, 9J, 9K, 9L, 9M, 9N, 9O: Mfap4 effect is conserved in human cells FIG. 9A) shRNAs were identified that efficiently targeting human Mfap4. Knockdown test by Western blot analysis using whole-cell lysates. HepG2 cells with stable expression of indicated shRNAs targeting human Mfap4 were generated by retroviral infection and selection. Tubulin serves as a loading control. FIG. 9B) EdU incorporation assay. DNA synthesis of HepG2 cells transfected with hushMfap4 and shNC was assessed by EdU assays. Quantification shows significant difference between experiment and control. FIG. 9C-9E) Transcriptomic analysis of liver samples from −150 patients shows increased Mfap4 expression in NAFLD patients with cirrhosis and fibrosis 4 score (Table: boxes indicate disease stages with significant change, but less than log 2 2 fold change; grey mark indicates significant upregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005). FIG. 9F) Human tissue samples from healthy and cirrhotic liver was stained for Mfap4 protein (Mfap4 specific antibody & DAB staining). On the left side healthy liver tissue was stained without primary antibody as a control. In the middle, the staining of healthy liver indicates hepatocytes are slightly positive for Mfap4. Interestingly we also see some nuclear staining. Right panel shows staining of cirrhotic human liver. Human hepatocytes show strong staining in cytoplasm as well as nuclear staining. On the left side of the cirrhotic liver fibrotic scar tissue can be seen and is highly positive for Mfap4. FIG. 9G) Knockdown test of human MFAP4 siRNA pool. Western blot analysis of protein extracts from immortalized human hepatocytes (Creative Bioarray CSC-19016L) either treated with si huMFAP4 or siNC., α-Tubulin serves as loading control (n=3). FIG. 9H) EdU incorporation assay shows greater number of EdU-positive cells in experiment compared to control. FIG. 91 ) EdU incorporation assay (3 technical replicates). Shown is the value of % EdU positive cells±SEM. Immortalized human hepatocytes were either treated with siRNA targeting human MFAP4 or siNC as control (*p<0.05). FIG. 9J) Scheme of retroviral backbone for generating stable cell lines. FIG. 9K) Representative GFP pictures of immortalized Human Hepatocytes (Creative Bioarray CSC-19016L) with stable integration of shRNAs against human Mfap4. FIG. 9L) qPCR analysis showing efficient knockdown of huMfap4 by two shRNAs—hu shMfap4.1812 (SEQ ID NO: 7100) and hu shMfap4.1602 (7097) compared to non-targeting control. FIG. 9M) Western blot showing efficient knockdown of human Mfap4 by two independent shRNAs in immortalized human hepatocytes-SV40. FIG. 9N) Mfap4 knockdown in human immortalized hepatocytes accelerates wound healing. Wound healing assay using immortalized human hepatocytes with stable expression of shhuMFAP4.1602 or shNC respectively. Cells were grown to full confluence, then the silicon gasket was removed leaving a defined cell free area (0 h). Filling of this “wound” gap was monitored (48 h; n=3 for each condition). FIG. 9O) Quantification of L), wound healing area (n=3; *p<0.05, ns=non-significant).

FIG. 10A, 10B, 10C, 10D: In vitro validation of targeting Grhpr for enhancing regeneration FIG. 10A) Outline of retroviral backbone for generating stable cell lines. FIG. 10B) Test of knockdown efficiency of top scoring shRNAs targeting Grhpr. Western blot showing efficient knockdown of Grhpr by our shRNAs (Alpha-tubulin, αTub functions as loading control). FIG. 10C) Wound healing assay. Stable cell lines were grown to full confluence, then the silicon gasket was removed leaving a defined cell free area. Filling of this “wound” gap was monitored. Representative images for each group are shown. FIG. 10D) Quantification over different time points of wound healing assay is shown (Data was analyzed by ImageJ software and 2-way ANOVA test of GraphPad Prism software. Significant difference between shGrhpr361 (SEQ ID NO: 3) and shNC is shown by ‘*’).

FIG. 11A, 11B, 11C, 11D, 11E, 11F, 11G: Grhpr knockdown accelerates liver repopulation FIG. 11A) Outline shows the transposon based vector for the expression of the enzyme FAH, the marker GFP and the shRNA of interest. FIG. 11B) FAH knockout mice based liver repopulation assay. Outline shows the rational for the assay. If the knockdown of a certain shRNA is able to enhance regeneration and accelerate hepatocyte proliferation, we should be able to see a faster clonal expansion compared to a control shRNA starting from the stably integrated hepatocytes. FIG. 11C) GFP imager images. GFP imaging of explanted mouse livers shows enhanced clonal expansion (repopulation) of hepatocytes stably expressing shGrhpr.361 (SEQ ID NO: 3) compared to hepatocytes expressing shNC (day 18 after HDTV injection of 25 μg of the indicated plasmid). Representative photographs are shown for each group (n=5). Light, white points represent GFP positive macroscopically visible clonal expansions. FIG. 11D) Native GFP on tissue sections. Shown are representative GFP fluorescence photographs of liver sections (200×) of FAH−/− mice 18 days after in vivo delivery of transposon constructs either expressing shGrhpr or a control shRNA corresponding to C). FIG. 11E) Histological analysis (immunostaining against GFP) for GFP-positive cells of mouse livers with stable expression of shGrhpr.361 (SEQ ID NO: 3) and shNC (shown are representative photographs, n=5 in group with shGrhpr.361, n=5 in group with shNC). Day 18 after HDTV injection of 1.25 μg of the indicated plasmid (200× magnification). Increased clonal expansion can be seen for shMfap4. FIG. 11F) Quantification of GFP-positive cells (corresponding to E)) shows significant increase in GFP positive hepatocytes in case of Mfap4 knockdown compared to control. Each dot represents one animal. FIG. 11G) Survival curve with dilution of constructs (1:30) as 0.83 μg plasmid and 0.17 mg SB13. All experimental mice with shGrhpr constructs (n=5) survived whereas control mice died (n=5).

FIG. 12A, 12B, 12C, 12D: Grhpr knockdown accelerates liver regeneration after partial hepatectomy FIG. 12A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that ⅔ of the liver was surgically removed. The remaining regenerating liver was harvested at different time points after surgery. FIG. 12B) Representative photographs of Ki67 DAB-stained liver sections (200× magnification) at 24 hours' (n=5 per group), 38 hours' (n=6 per group), 48 hours' (n=9 per group) time points after partial hepatectomy. Earlier and increased hepatocyte proliferation after partial hepatectomy in shGrhpr-expressing livers compared to shNC livers can be seen. FIG. 12C) Quantification of Ki67 positive cells of DAB-stained liver sections (corresponding to B)) show earlier and increased hepatocyte proliferation after partial hepatectomy in shGrhpr-expressing livers compared to shNC livers (individual points represent individual animals, data shows average±SEM). FIG. 12D) Schematic representation of peak shifting of mitotic cycle in case of Grhpr knockdown compare to control shNC (corresponding to C)).

FIG. 13A, 13B, 13C, 13D: Grhpr knockdown attenuates chronic liver damage related liver fibrosis FIG. 13A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that chronic liver damage was induced by repetitive doses of thioacetamide administered intraperitoneal 3 times per week for 8 weeks. Livers were harvested, processed and analyzed. FIG. 13B) Representative macro-photographs of the livers are shown. Already macroscopically differences between groups were visible. FIG. 13C) Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (n=5 per each group, 50× magnification). FIG. 13D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental groups.

FIG. 14A, 14B, 14C, 14D: Grhpr knockdown does not protect against NASH related liver fibrosis FIG. 14A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After full repopulation was reached mice were exposed to the “Western Diet” (high fat diet and 60% fructose) for 24 weeks. Livers were harvested, processed and analyzed. FIG. 14B) Representative macro-photographs of the livers are shown. FIG. 14C) Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (n=6 per experimental group and n=7 per control group; representative sections are shown, 50× magnification). FIG. 14D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental group.

FIG. 15A, 15B, 15C: Grhpr expression changes in human NAFLD A) Transcriptomic analysis of liver samples from ˜150 patients shows slight but significant decrease in Grhpr expression in NASH patients with advanced fibrosis and cirrhosis. Consistent with this we detected a significant reduction in patients with

fibrosis

3 and 4 score (* p<0.05, ** p<0.01, ***p,0.005).

FIG. 16A, 16B, 16C, 16D, 16E, 16F, 16G, 16H: Itfg1 knockdown accelerates wound healing and liver repopulation FIG. 16A) Outline of retroviral backbone for generating stable cell lines. FIG. 16B) Test of knockdown efficiency of top scoring shRNAs targeting Itfg1. qPCR analysis and Western blot analysis show efficient knockdown of Itfg1 by our shRNAs. FIG. 16C) Itfg1 knockdown accelerates wound healing in vitro. Stable cell lines were grown to full confluence, then the silicon gasket was removed leaving a defined cell free area. Filling of this “wound” gap was monitored. Representative images are shown in upper part. Quantification over different time points of wound healing assay is shown (lower part, Data was analyzed by ImageJ software and 2-way ANOVA test of GraphPrizm software. Significant difference between shltfg1.698 (SEQ ID NO: 6), shltfg1.680 (SEQ ID NO: 7) and shNC is shown by ‘*’). FIG. 16D) Outline shows the transposon-based vector for the expression of the enzyme FAH, the marker GFP and the shRNA of interest (upper panel). Lower panel shows FAH knockout mice based liver repopulation assay. Outline shows the rational for the assay. If the knockdown of a certain shRNA is able to enhance regeneration and accelerate hepatocyte proliferation, we should be able to see a faster clonal expansion compared to a control shRNA starting from the stably integrated hepatocytes. FIG. 16E) GFP imager images. GFP imaging of explanted mouse livers shows enhanced clonal expansion (repopulation) of hepatocytes stably expressing shltfg1 compared to hepatocytes expressing shNC (day 18 after HDTV injection of 1.25 μg of the indicated plasmid; representative photographs are shown; n=8 per experimental group with knockdown by shltfg1.698, n=6 per experimental group with knockdown by shltfg1.680, and n=6 per control group). Light, white points represent GFP positive macroscopically visible clonal expansions. FIG. 16F) Histological analysis (immunostaining against GFP) for GFP-positive cells of mouse livers with stable expression of shltfg1.698, shltfg1.680 and shNC (shown are representative photographs). Day 18 after HDTV injection of 1.25 μg of the indicated plasmid (200× magnification). Increased clonal expansion can be seen for shltfg1. FIG. 16G) Quantification of GFP-positive cells (corresponding to F)) shows significant increase in GFP positive hepatocytes in case of Itfg1 knockdown compared to control. Each dot represents one animal. FIG. 16H) Repopulation survival assay. The right panel shows the outline of the experiments. We further diluted the plasmid amount delivered to the liver. At a certain dilution the amount of hepatocytes with stable integration will be not enough to expand and compensate for the loss of FAH−/− hepatocytes. However, if the knockdown by our candidate accelerates repopulation it might be sufficient to compensate and allow survival. Left panel shows the survival curve after 1:30 dilution. All animals injected with our construct expressing the control shRNA died, whereas all mice injected with our construct expressing shltfg1 survived. There is statistical significance between experiment and control. Statistical significance was calculated using a log rank test (n=5 per group).

FIG. 17A, 17B, 17C, 17D, 17E: Itfg1 knockdown attenuates chronic liver damage related liver fibrosis FIG. 17A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that chronic liver damage was induced by repetitive doses of thioacetamide administered intraperitoneal 3 times per week for 8 weeks. Livers were harvested, processed and analyzed. FIG. 17B) Representative macro-photographs of the livers are shown. Already macroscopically differences between groups were visible. FIG. 17C) Picro Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (n=6 for shltfg1.698 and n=7 for control group, 50× magnification). FIG. 17D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental groups. FIG. 17E) Representative macro-photographs of the livers with GFP-imaging system is shown. Livers are all green, hence fully repopulated.

FIG. 18A, 18B, 18C, 18D, 18E, 18F, 18G, 18H, 18I: ITFG1 expression in human liver tissue; knockdown protects against NASH related fibrosis (see also FIG. 35A-35F). FIG. 18A) Macroscopic pictures of mice with repopulated liver exposed to Western Diet. shltfg1 indicates liver was repopulated so that every hepatocyte expresses the shRNA targeting Itfg1, whereas shNC indicates repopulation so that every hepatocyte expresses a non-targeting control shRNA. Already macroscopically, livers with Itfg1 knockdown show reduced fibrosis. FIG. 18B-18D) Transcriptomic analysis of liver samples from ˜150 patients show no significant expression change for Itfg1. FIG. 18E) ITFG1 is expressed in healthy liver tissue and in NASH Cirrhosis. FIG. 18F) Expression of ITFG1 in human tissues is shown. Data is taken from The Human Protein Atlas. FIG. 18G) Low expression of ITFG1 is associated with longer survival in case of liver cancer. Data is taken from The Human Protein Atlas. FIG. 18H) Scheme of retroviral backbone for generating stable cell lines. FIG. 181 ) shRNAs efficiently targeting human ITFG1 were identified. Knockdown test by Western blot analysis using whole-cell lysates. HepG2 cells stably expressing the shRNA of interest were generate by retroviral infection and selection. GAPDH serves as a loading control.

FIG. 19A, 19B, 19C, 19D: EMULSION +500 in vivo functional genetic screen FIG. 19A) Schematic outline of the screen. A pooled shRNA library screen targeting 467 genes, dysregulated in human NAFLD patients, is set up. The screen is conducted in mice of both gender using two diet based NAFLD models. FIG. 19B) Representation of fold change for each shRNA passing a p-value of 0.1 from male mice exposed to choline-deficient L-amino acid defined high fat diet for 8 weeks. The majority of shRNAs is deplete but a small number is clearly enriched. FIG. 19C) Principal component analysis based on normalized shRNA abundance level. We can see a clear separation based on diet exposure. FIG. 19D) Heatmap based enrichment/depletion for each animal for top-enriched and depleted shRNAs. Based on our analysis we identified 6 high confidence targets.

FIG. 20A, 20B: CDHFD mouse fatty liver model FIG. 20A) Choline deficient L-amino acid defined high fat diet (CDHFD) leads to fast and progressive fatty liver disease in mice. Already after 8 weeks of diet exposure mice show NASH with advanced fibrosis. FIG. 20B) Pathological evaluation. Histological slides of liver tissue form C56B16 mice exposed to the indicated time to the CDHFD or normal chow were evaluated and scored by a certified pathologist. Shown are the scoring results for steatosis and fibrosis. Each point represents an animal.

FIG. 21A, 21B, 21C, 21D, 21E: Abcc4 is a potential therapeutic target for NAFLD FIG. 21A) Shown is the relative read numbers for the shRNA expression cassette targeting Abcc4 for each animal (NC=normal chow, CD=CDHFD). FIG. 21B) Summary of screening result for the shRNA expression cassette targeting Abcc4. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 21C-21E) Transcriptomic analysis of liver samples from ˜150 patients show significant increase in Abcc4 gene expression at NASH late fibrosis and cirrhosis stage. Furthermore, an increase expression can be detected based on ballooning and fibrosis stage (Table: grey mark indicates significant upregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005).

FIG. 22A, 22B, 22C, 22D, 22E: Pak3 is a potential therapeutic target for NAFLD FIG. 22A) Shown is the relative read numbers for the shRNA expression cassette targeting Pak3 for each animal (NC=normal chow, CD=CDHFD). FIG. 22B) Summary of screening result for the shRNA expression cassette targeting Pak3. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 22C-22E) Transcriptomic analysis of liver samples from ˜150 patients show significant increase in Pak3 gene expression at NASH cirrhosis stage. Furthermore, an increase expression can be detected based on fibrosis stage (Table: grey mark indicates significant upregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005).

FIG. 23A, 23B, 23C, 23D, 23E: Trnp1 is a potential therapeutic target for NAFLD FIG. 23A) Shown is the relative read numbers for the shRNA expression cassette targeting Trnp1 for each animal (NC=normal chow, CD=CDHFD). FIG. 23B) Summary of screening result for the shRNA expression cassette targeting Trnp1. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 23C-23E) Transcriptomic analysis of liver samples from −150 patients show significant increase in Trnp1 gene expression at NASH cirrhosis stage. Interestingly, with increased steatosis and inflammation expression seems to be downregulated (Table: grey mark indicates significant upregulation of at least log 2 2 fold; boxed grey mark indicates significant downregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005).

FIG. 24A, 24B, 24C, 24D, 24E: Apln is a potential therapeutic target for NAFLD FIG. 24A) Shown is the relative read numbers for the shRNA expression cassette targeting Apln for each animal (NC=normal chow, CD=CDHFD). FIG. 24B) Summary of screening result for the shRNA expression cassette targeting Apln. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 24C-24E) Transcriptomic analysis of liver samples from ˜150 patients show significant increase in Apln gene expression at NASH cirrhosis stage. Interestingly, with increased inflammation expression seems to be downregulated (Table: grey mark indicates significant upregulation of at least log 2 2 fold; boxed grey mark indicates significant downregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005).

FIG. 25A, 25B, 25C, 25D, 25E: Kif20a is a potential therapeutic target for NAFLD FIG. 25A) Shown is the relative read numbers for the shRNA expression cassette targeting Kif20a for each animal (NC=normal chow, CD=CDHFD). FIG. 25B) Summary of screening result for the shRNA expression cassette targeting Kif20a. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 25C-25E) Transcriptomic analysis of liver samples from ˜150 patients show a progressive increase in Kif20a gene expression till the NASH advanced fibrosis stage (Table: grey mark indicates significant upregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005)

FIG. 26A, 26B, 26C, 26D, 26E: Ltb is a potential therapeutic target for NAFLD FIG. 26A) Shown is the relative read numbers for the shRNA expression cassette targeting Ltb for each animal (NC=normal chow, CD=CDHFD). FIG. 26B) Summary of screening result for the shRNA expression cassette targeting Ltb. Shown are the average relative reads for each group, the fold change and the log 2 fold change comparing CDHFD mice to NC mice. FIG. 26C-26E) Transcriptomic analysis of liver samples from ˜150 patients show a progressive increase in Ltb gene expression till the NASH advanced fibrosis stage (Table: grey mark indicates significant upregulation of at least log 2 2 fold; * p<0.05, ** p<0.01, ***p,0.005).

FIG. 27 : Layout for NASH disease interception in vivo functional genetic screen FIG. 27 ) A genome wide in vivo functional genetic screen for disease interception. Nearly 80.000 shRNAs split into 32 sub-pools are screened. ShRNA expresses ion is inducible and only activated after liver shows steatosis but before NASH progression.

FIG. 28A, 28B, 28C, 28D, 28E: Mfap4 knockdown for 1 year does not lead to liver cancer FIG. 28A) Schematic representation of the experiment. FAH−/− mice were injected with p/T-FAHIG-shRNA & SB13 expressing constructs via HDTV; then, mice were kept for 1 year to observe any tumor formation or abnormal liver histology. FIG. 28B) Bright field. Representative pictures are shown (both surfaces of the liver) (n=5 mice per experimental group, n=5 mice per control group). FIG. 28C) GFP-imaging. Representative pictures are shown (both surfaces of the liver). No GFP-positive tumor is observed. Livers are fully repopulated (strong GFP-positive signal). FIG. 28D) Hematoxylin & Eosin staining. Representative pictures are shown. No malignant disease is observed in both: experimental group and control group. Pathology evaluation is conducted by certified pathologist. The pathologist did not find malignant lesions in the liver. FIG. 28E) GFP (DAB) staining. Representative pictures are shown. Around 95% of hepatocytes are GFP-positive which means livers were fully repopulated.

FIG. 29A, 29B, 29C: GalNAC conjugates with siRNA against Mfap4 (BNL CL.2 cell line; 72 h post-transfection) FIG. 29A) Structure of GalNAC-siRNA conjugate used in studies. Exact backbone modifications can be found in the sequence appendix (SEQ ID NOs: 7092 and 7093). The target sequence for the siRNA was based on the shRNA guide sequence. FIG. 29B) Western blot analysis with concentration 6 μM shows efficient knockdown of Mfap4 by two different conjugates GalNAC-si Mfap4.1356 (SEQ ID NOs: 7092) and GalNAC-si Mfap4. 760 (SEQ ID NOs: 7093) compared to control. FIG. 29C) Western blot analysis with concentration 11 μM shows efficient knockdown of Mfap4 by two different conjugates GalNAC-si Mfap4.1356 and GalNAC-si Mfap4. 760 compared to control.

FIG. 30A, 30B, 30C: Grhpr knockdown for 1 year does not lead to liver cancer FIG. 30A) Schematic representation of the experiment. FAH−/− mice were injected with p/T-FAHIG-shRNA & SB13 expressing constructs via HDTV; then, mice were kept for 1 year to observe any tumor formation or abnormal liver histology. Livers were harvested at 1 year after injections. FIG. 30B) Bright field. Representative pictures are shown (both surfaces of the liver) (n=3 mice per experimental group, n=5 mice per control group). FIG. 30C) GFP-imaging. Representative pictures are shown (both surfaces of the liver). No GFP-positive tumor is observed. Livers are fully repopulated (strong GFP-positive signal).

FIG. 31A, 31B, 31C: Grhpr expression in human hepatocytes (HpG2 cell line) FIG. 31A) Scheme of retroviral backbone for generating stable cell lines. FIG. 31B) shRNAs efficiently targeting human Grhpr were identified. Knockdown test by qPCR using whole-cell lysates. HepG2 cells were cotransfected with pMSCV vector. FIG. 31C) Knockdown test by Western blot using whole-cell lysates. HepG2 cells with stable expression of indicated shRNAs were generated by retroviral infection and selection. Tubulin serves as a loading control.

FIG. 32A, 32B: GalNAC conjugates with siRNA against Grhpr (BNL CL.2 cell line; 72 h post-transfection) FIG. 32A) Structure of GalNAC-siRNA conjugate used in studies. Exact backbone modifications can be found in the sequence appendix (SEQ ID NO: 7094). The target sequence for the siRNA was based on the shRNA guide sequence. FIG. 32B) Western blot analysis with concentration 6 μM shows efficient knockdown of Grhpr by conjugate GalNAC-si Grhpr.361 (SEQ ID NO: 7094) compared to scrambled control. Western blot analysis with concentration 11 μM shows efficient knockdown of Grhpr by conjugate GalNAC-si Grhpr.361 compared to scrambled control.

FIG. 33A, 33B, 33C: Itfg1 knockdown accelerates liver regeneration after partial hepatectomy (PH) FIG. 33A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After that ⅔ of the liver was surgically removed. The remaining regenerating liver was harvested at 42 h and 48 h after surgery. FIG. 33B) Representative photographs of DAB Ki67-stained liver sections 42 h (n=4 per experimental group, n=6 per control group) and 48 h (n=5 per experimental group, n=10 per control group) post hepatectomy are shown (200× magnification). FIG. 33C) Quantification of Ki67 positive cells of DAB-stained liver sections (corresponding to B) show increased hepatocyte proliferation after partial hepatectomy in shltfg1-expressing livers compared to shNC livers (individual points represent individual animals, data shows average±SEM).

FIG. 34A, 34B, 34C, 34D, 34E, 34F, 34G: Itfg1 knockdown for 1 year does not lead to liver cancer FIG. 34A) Schematic representation of the experiment. FAH−/− mice were injected with p/T-FAHIG-shRNA & SB13 expressing constructs via HDTV; then, mice were kept for 1 year to observe any tumor formation or abnormal liver histology. Livers were harvested at 1 year after injections. FIG. 34B) Bright field. Representative pictures are shown (both surfaces of the liver). No tumor is observed (n=5 mice per experimental group, n=5 mice per control group). FIG. 34C) GFP-imaging. Representative pictures are shown (both surfaces of the liver). No GFP-positive tumor is observed. Livers are fully repopulated (GFP-positive). FIGS. 34D and 34F) Hematoxylin & Eosin staining. Representative pictures are shown. No malignant disease is observed in both: experimental group and control group. Pathology evaluation is conducted by certified pathologist. FIGS. 34E and 34G) GFP (DAB) staining. Representative pictures are shown. Around 95% of hepatocytes are GFP-positive which means livers were fully repopulated.

FIG. 35A, 35B, 35C, 35D, 35E, 35F: Itfg1 knockdown attenuates chronic liver damage related liver fibrosis in a NASH model FIG. 35A) Experimental outline. FAH−/− mice were injected with our constructs, then, mice were kept for full repopulation for 3 months. After full repopulation was reached mice were exposed to the “Western Diet” (high fat diet and 60% fructose) for 24 weeks. Livers were harvested, processed and analyzed. FIG. 35B) Representative macro-photographs of the livers are shown. Already macroscopically differences between groups were visible. FIG. 35C) Picro Sirius Red staining (staining for fibrotic scar tissue) and Hematoxylin & Eosin staining on sections of indicated repopulated mouse livers (representative images are shown; n=6 for shltfg1.698 and n=7 for control group, 50× magnification). FIG. 35D) The fibrotic score for each animal is shown. The score was given by a certified pathologist, who was blinded regarding the experimental groups. FIG. 35E) Objective, Al-based analysis of steatosis done by HistoIndex. Representative pictures are shown. FIG. 35F) Quantification analysis shows significantly lower steatosis score in experimental group (n=7 mice per group) compared to control group (n=7 mice per group).

FIG. 36A, 36B, 36C: Knockdown of Itfg1 impacts MKK6, JNK, and RPS6 signaling FIG. 36A) Schematic outline of isolating proteins from full repopulated livers for further broad protein array analysis. FIG. 36B) After performing a broad protein array focused Western blot experiments were done. Results of Western blot are shown here. Proteins from fully repopulated livers were isolated. Especially P-MKK6/P-MKK3 are greater activated in case of Itfg1 knockdown compared to control. There are 3 biological replicates in experiment and 3 biological replicates in control. FIG. 36C) According to STRING database, all indicated proteins are interacting and are linked to cell growth and proliferation.

FIG. 37A, 37B: GalNAC conjugates with siRNA against Itfg1 (BNL CL.2 cell line; 72 h post-transfection) FIG. 37A) Structure of GalNAC-siRNA conjugate used in studies. Exact backbone modifications can be found in the sequence appendix (SEQ ID NOs: 7095 and 7096). The target sequence for the siRNA was based on the shRNA guide sequence. FIG. 37B) Western blot analysis with concentration 6 μM shows efficient knockdown of Itfg1 by two different conjugates GalNAC-si Itfg1.698 (SEQ ID NO: 7095) and GalNAC-si Itfg1.680 (SEQ ID NO: 7096) compared to control. Western blot analysis with concentration 11 μM shows efficient knockdown of Itfg1 by two different conjugates GalNAC-si Itfg1.698 and GalNAC-si Itfg1.680 compared to control.

FIG. 38A, 38B, 38C: Mfap4 and Itfg1 knockdown enhances proliferation and regeneration beyond liver FIG. 38A) Outline of the wound healing assay. Stable cell lines were generated expressing the respective shRNAs. FIG. 38B) Knockdown of Mfap4 as well as the knockdown of Itfg1 accelerates wound healing of mouse lung cells (cell line CCL206). FIG. 38C) Knockdown of Mfap4 as well as the knockdown of Itfg1 accelerates wound healing of mouse myoblast cells (Myoblast cell line CRL1772).

FIG. 39 : Pak3 knockdown accelerates wound healing in vitro Stable knockdown of Pak3 in AML12 adult hepatocyte cell line accelerates wound healing (representative images are shown).

EXAMPLES

Example 1 Functional Genetic In Vivo RNAi Screen

An in vivo functional genetic screen was conducted to identify new modulators of liver regeneration as therapeutic targets to increase endogenous regeneration and counteract liver disease. This approach was originally pioneered by taking advantage of FAH−/− mice. From there the screening set up was further modified and improved, so it can be applied to any mouse independent of genetic background and modification (FIG. 1A). A focused shRNA library was delivered, comprising of 250 shRNAs targeting 89 genes, by hydrodynamic tail vine injection to the liver. Through the combination with a plasmid encoding for the sleeping beauty 13 transposase, stable integration was obtained in around 5 to 10% of hepatocytes. Therefore, a chimeric mouse liver in which the shRNA expressing hepatocytes are surrounded by “wt” hepatocytes is generated. To simulate chronic liver damage the inventors treated 3 times per week for 8 weeks mice with thioacetamid (TAA), a chemical inducing liver damage (FIG. 1A). Cycles of liver damage and compensatory regeneration induce a competitive environment. If the knockdown by a certain shRNA gives an advantage to hepatocytes, the cells will expand and an enrichment for the shRNA can be detected. In contrast, if the expression of a shRNA is detrimental, this shRNA should deplete. No change compared to the starting pool indicates no effect in this environment. The abundance of the shRNAs can be determined by Illumina based deep sequencing. For sequencing, the genomic DNA was isolated from the liver, the shRNA expressing cassette was amplified with primers including Illumina adapter sequences and the product was directly sequenced.
Also, the majority of the shRNAs were depleted in this screen, a subset was consistently enriched in all biological replicates (5 independent mice) (FIG. 1B-1C). Importantly and giving confidence in the screen, two independent non-targeting control shRNAs (also named shNC or shCTRL; one targeting renilla and one targeting luciferase, both are not expressed in mice) were not enriched or depleted. Furthermore, three independent shRNAs targeting c-Met the receptor for hepatocyte growth factor and essential for liver regeneration were depleted (FIG. 1D). To avoid off-target effects of the shRNAs the inventors focused on targets against which at least two independent shRNAs were enriched (FIG. 1D). Four independent shRNAs were found enriched targeting Mfap4, two independent shRNAs for each targeting Grhpr and Itfg1.

Example 2 Validation of Identified Therapeutic Targets

Mfap4—Microfibril Associated Protein 4
For validation, the knockdown efficiency of the two top-enriched shRNAs targeting Mfap4 in vitro were first tested (FIG. 2A). Both shRNAs show efficient knockdown. For each shRNA stable expressing cell lines (FIG. 2B) were generated as well as for a non-targeting control shRNA and the effect of the shRNAs in a wound healing assay was tested. The knockdown of Mfap4 (two independent shRNAs tested) increased wound closure in TIB 73 (BNLCL.2) cells and AML 12 cells, indicating increased proliferation (FIGS. 2C and 2G). Furthermore, using the stable cell lines the inventors checked for enhanced cell replication by EdU incorporation and determining the cell doubling time (FIG. 2D-2E). Accelerated proliferation was clearly detected. Cell cycle analysis by flow cytometry using the Guava Muse Cell Analyzer showed greater cell amounts (shown is amount of cell in %) in the G2 phase of cell cycle for cells with stable Mfap4 knockdown by shMfap4.1356 (SEQ ID NO: 1) and shMfap4.760 (SEQ ID NO: 2) compared to the non-targeting control (shNC), likewise indicating increased proliferation (FIG. 2F).
The inventors then took advantage of the FAH (fumarylacetoacetate) knock out mouse. The defect in the tyrosine metabolism leads to the accumulation of toxic side products in hepatocytes resulting in liver failure. Delivering a construct to around 5-10% of hepatocytes for the expression of the missing enzyme FAH and the shRNAs by hydrodynamic tail vine injection, the repopulation efficiency could be tested. If the knockdown by the shRNA targeting Mfap4 enhances regeneration and proliferation, a faster clonal expansion should be seen (FIG. 3A). As expected, knockdown of Mfap4 enhances repopulation detected by GFP-imaging of the whole liver (FIG. 3B), native-GFP fluorescence of cryosections (FIG. 3C) of the liver and antibody based staining for GFP in paraffin sections (FIG. 3D-3E). A further dilution of the amount of injected plasmids could reduce the amount of hepatocytes with stable expression of FAH, GFP and the shRNA of interest, so that the FAH expressing hepatocytes cannot fast enough expand and compensate for FAH−/− hepatocyte loss. However a shRNA dependent acceleration of regeneration might be able to allow survival. At a 1:30 dilution still all shMfap4.1356 (SEQ ID NO: 1) injected mice survive whereas all control shNC injected mice die (FIG. 3F). This further supports the Mfap4 knockdown mediated acceleration, as only in case of Mfap4 the hepatocytes expand fast enough to compensate for hepatocyte loss.
The “Western Diet” induces progressive NAFLD, leading to NASH and fibrosis (FIG. 4 ). The inventors repopulated FAH−/− mouse liver so that all hepatocytes express either a shRNA targeting Mfap4 or a non-targeting control shRNA. After full repopulation, the mice were exposed to the “Western Diet” (FIG. 5A). Knockdown of Mfap4 clearly attenuates disease progression, reflected in reduced fibrosis (FIG. 5B-5F). Chronic TAA exposure to shMfapp4 and shCTRL repopulated FAH mice (FIG. 6A) was also applied. Consistent with the screening results Mfap4 knockdown protects against TAA induced liver damage and fibrosis (FIG. 6B-6D). As an acute damage model, a ⅔ partial hepatectomy (PH) on repopulated mice (FIGS. 7A and 7E) was performed. Enhanced Ki67 staining (FIGS. 7B-7C and 7F-7G) as well as earlier activation of cyclin A (FIG. 7D) and cyclin E (FIG. 7H), respectively, after PH indicate faster regeneration. GFP-imaging (FIG. 7I) and DAB GFP staining (FIG. 7J) of FAH−/− livers after ⅔ surgical partial removal of livers indicated that mice were fully repopulated.
The inventors also checked for differences in pathway activation by protein arrays and Western blot after full repopulation with either shMfap4 or non-targeting control shRNA. Livers were collected and proteins for protein array and Western blot as well as RNA for transcriptomics were isolated (FIG. 8A-8H). Consistently with an enhanced regenerative capacity Mfap4 knockdown induces activation of mTOR, p70S6K, ERK and p38 (FIGS. 8B and 8D). The identified pathways are all linked (FIGS. 8C, 8E and 8K) based on STRING analysis (string-db.org) and impact cell growth and proliferation. P70S6K is a major substrate of mTOR (FIG. 8E) and contributes to liver regeneration. Furthermore, impairments in p70S6K and ERK signaling is linked to the age dependent decline of liver's regenerative capacity. Using the in vitro wound healing assay, double knockout experiments combining the stable shMfap4 or shCTRL expressing cell lines with siRNAs targeting either p70s6k or p38 (FIG. 8F-8G) were conducted. A slowdown in wound healing under such conditions was detected. This puts the knockdown of Mfap4 in line with enhancing regeneration and rejuvenating the liver. Principal component analysis for AML12-shMfap4.1356, AML12-shMfap4.760, and AML12-shNC shows cluster separation between experiment (shMfap4) and control (shNC). A heatmap comparison of Mfap4 and control indicates that genes known to be involved in liver regeneration according to the literature, such as Ptgs2, Areg, Dhrs9, Hmox1 and Nqo1, are upregulated after Mfap4 knockdown compared to control (FIG. 8H-8J). Furthermore, string analysis shows that the transcriptomic pathways coming from the cell line as well as the proteomic identified pathways from the repopulated liver are connected (FIG. 8K).
The inventors then identified 2 independent shRNAs targeting human Mfap4: huMfap4.1812 (SEQ ID NO: 7100) and huMfap4.1602 (SEQ ID NO: 7097). Efficient knockdown in the human liver cancer cell line HepG2 (FIG. 9A) was observed. Furthermore, both shRNAs show a strong on-target knockdown of huMfap4 compared to non-targeting control as determined by qPCR analysis (FIG. 9K) and Western blot (FIG. 9L) in immortalized human hepatocytes-SV40 (FIG. 91-9J). Edu incorporation assay indicates a conserved mechanism between mouse and human, as higher EdU incorporation in human HepG2 cells with Mfap4 knockdown was seen (FIG. 9B), transient knockdown of Mfap4 by siRNA in immortalised human hepatocytes shows higher EdU incorporation (FIG. 9G-9H), and stable knockdown of Mfap4 in immortalised human hepatocytes enhances wound healing (FIG. 9M-9N).
Importantly expression of Mfap4 in the liver increases in NAFLD patients with cirrhosis (FIG. 9C-9D), based on a local patient cohort. This is consistent with previous studies indicating increased Mfap4 in liver and lung fibrosis. Interestingly, Mfap4 was suggested as potential biomarker for non-invasive assessment of hepatic fibrosis in hepatitis C patients. Staining for Mfap4 of human liver tissue from healthy and cirrhotic liver done by the inventors also showed increased detection in the diseased liver. Interestingly beside strong staining in fibrotic scar areas Mfap4 was also detected in the cytoplasm and nucleus of hepatocytes (FIG. 9E). Mfap4 is thought to be an extracellular matrix protein but not much is known about its role in hepatocytes. It represents therefore a new target for liver disease therapy, with new biology.
The inventors also investigated the development of liver cancer in Mfap4 treated mice. shMfap4 constructs were delivered by HDTV to FAH−/− mice. After keeping mice for 1 year, livers were harvested to determine any tumor formation in the liver (FIG. 28A). No GFP-positive tumor is observed and livers are fully repopulated as indicated by a strong GFP-positive signal (FIGS. 28B-28C and 28E). Around 95% of hepatocytes are GFP-positive. Also, Hematoxylin & Eosin staining did not reveal any malignant disease in both the shMfap4 and shNC treated group. Certified pathologists who conducted the evaluation did not find malignant lesions in the liver (FIG. 28D). The experiments show that Mfap4 knockdown for 1 year does not lead to liver cancer in mice.
Modified siRNA-GalNAC conjugates targeting Mfap4 were generated (FIG. 29A; Table 11; SEQ ID NOs: 7092 and 7093). Human immortalised hepatocytes were treated for 72 h with siRNA and were then exposed for 4 h to EdU, then fixed and analysed. Western blot analysis with shows efficient knockdown of Mfap4 by two different conjugates GalNAC-si Mfap4.1356 and GalNAC-si Mfap4.760 compared to scrambled control.
Grhpr—Qlyoxylate and Hydroxypyruvate Reductase
The second identified target is an enzyme with hydroxyl-pyruvate reductase, glyoxylate reductase and D-glycerate dehyrdrogenase enzymatic activities. Two shRNAs targeting Grhpr were strongly enriched in the screen (FIG. 1A-1D). Validation followed the same way as was described for Mfap4. First, stable cell lines were generated and the knockdown efficiency of the shRNAs was determined (FIG. 10A-10B). Both shRNAs show a strong on-target knockdown. The wound healing assay supported a faster healing and faster proliferation under Grhpr knockdown condition (FIG. 10C-10D). Again, taking advantage of the FAH−/− mice, repopulation between Grhpr targeting and control shRNA was compared. Grhpr knockdown accelerates liver repopulation under these conditions and all shGrhpr injected mice still survive at a 1:30 dilution whereas all control shNC injected mice die (FIG. 11A-11G). Next, the liver was completely repopulated so that every hepatocyte expresses shGrhpr or a non-targeting control shRNA (FIG. 12A). In the acute liver damaging model of ⅔ partial hepatectomy, Grhpr knockdown accelerates regeneration indicated by the earlier peak of Ki67 positive cells (FIG. 12B-12D). Furthermore, applying chronic TAA treatment to shGrhpr expressing repopulated FAH−/− mouse liver showed reduced liver injury and reduced fibrosis compared to control (FIG. 13A-13D). However, Grhpr knockdown does not seem to protect against NAFLD related disease progression and fibrosis development in the Western Diet mouse model (FIG. 14A-14D).
Interestingly, the NAFLD patient cohort showed a significant reduction in Grhpr expression in the liver at NASH advanced fibrosis and cirrhosis stages, but not very strongly (FIG. 15A-15C).
Similar to the experimental set up for targeting Mfap4, the development of liver cancer was investigated under Grhpr knockdown conditions (FIG. 30A). FAH−/− mice were injected with a combination of p?T-FAHIG-shGrhpr and SB13 plasmids for liver repopulation. Initially 5 to 10% of hepatocytes will have stable integration. After NTBC drug withdrawal after injection the liver will be repopulated, so that nearly every hepatocyte will express the shRNA targeting Grhpr. 1 year after injection livers were harvested and evaluated for liver tumor development. No GFP-positive tumor were observed in FAH−/− mice, and livers are fully repopulated (FIG. 30B-30C), indicating that long term Grhpr knockdown in the liver does not induce liver cancer and is safe
Furthermore, HepG2 cells with stable expression of shRNAs were generated by retroviral transfection and selection (FIG. 31A). Grhpr knockdown was determined by qPCR and Western blot using RNA or whole-cell lysates (Tubulin was used as a loading control). Several independent shRNAs targeting human Grhpr were identified (FIG. 31 B) that lead to efficient Grhpr knockdown in the human liver cancer cell line HepG2 (FIG. 31C).
Modified siRNA-GalNAC conjugates targeting Grhpr were generated (FIG. 32A, Table 11; SEQ ID NO: 7094), following the same way as was described for Mfap4. BNL CL.2 cell line; 72 h post-transfection. Western blot analysis with 6 μM and 11 μM, respectively, shows efficient knockdown of Grhpr by conjugate GalNAC-si Grhpr.361 compared to scrambled control.
Itfg1—Integrin Alpha FG-GAP Repeat Containing 1
The on-target knockdown efficiency of the top enriched shRNA and an additional independent shRNA were first tested. Both shRNAs show a good on-target knockdown by qPCR and Western blot (FIG. 16A-16B). Itfg1 knockdown strongly accelerates wound healing in vitro, taking advantage of the stable cell lines (FIG. 16C). The inventors then took advantage of the FAH−/− mice and did a repopulation assay (FIG. 16D). Consistent with the screening results, both Itfg1 knockdowns accelerate repopulation (FIG. 16E-16G). Interestingly, if the plasmid input was further diluted, at some point, the amount of hepatocytes with stable integration should be not sufficient to compensate for hepatocyte loss after NTBC withdrawal (FIG. 16H right panel). At a 1:30 dilution still all shltfg1 injected mice survive whereas all shCTRL injected mice die (FIG. 16H left panel). This further supports the Itfg1 knockdown mediated acceleration, as only in case of shltfg1 the hepatocytes expand fast enough to compensate for hepatocyte loss. Consistent with this, after full liver repopulation, a protective effect of Itfg1 knockdown against chronic TAA induced liver damage and fibrosis (FIG. 17A-17E) was seen.
In the mouse Western Diet NAFLD model (FIG. 35A), knockdown of Itfg1 attenuates fibrosis development (FIG. 35B-35F), which could already be seen macroscopically (FIG. 18A). The rough surface on the liver of mice expressing a non-targeting control shRNA indicates advanced fibrosis. In contrast the surface of shltfg1 expressing livers indicates strong reduction in fibrosis. In addition objective analysis by HistoIndex with a proprietary AI pathology system, further showed significant reduction in steatosis by Itfg1 knockdown (FIG. 35E-35F). The expression data from our NAFLD patient cohort indicates no major expression changes in the liver during disease progression (FIG. 18B), suggesting a postransciptional regulation. Itfg1 is expressed in healthy liver tissue and in NASH, Cirrhosis and hepatocellular carcinoma (FIG. 18C-18E). Data from The Human Protein Atlas show that low expression of Itfg1 is associated with increased survival in liver cancer patients (FIG. 18G). Interestingly, so far not much is known about Itfg1 and therefore it represents an interesting novel target for liver disease. Generating stable human HepG2 cell lines and determining the knockdown efficiency of different Itfg1 shRNAs showed a strong on-target knockdown (FIG. 18G-18H) for human Itfg1.
Again, taking advantage of the FAH−/− mice, the liver was completely repopulated for 3 months so that every hepatocyte expresses shltfg1 or a non-targeting control shRNA (shNC). Afterwards, ⅔ of the liver was removed and liver regeneration monitored (FIG. 33A). In the acute liver damaging model of ⅔ partial hepatectomy, Itfg1 knockdown accelerates regeneration after partial hepatectomy indicated by an earlier peak and higher amount of Ki67 positive cells (FIG. 33B-33C). No malignant disease and no GFP-positive tumor is observed 1 year after Itfg1 knockdown in mice (FIG. 34A-34E). Livers are fully repopulated in both the shltfg1 group and control group as indicated by around 95% GFP-positive hepatocytes.
To investigate the differences in pathway activation after full repopulation with either shltfg1 or non-targeting control shRNA, proteins from full repopulated livers were isolated for further broad protein array analysis (FIG. 36A). After performing the broad protein array, focused Western blot experiments were carried out. It was observed that knockdown of ITFG1 impacts MKK6, JNK, and RPS6 signaling. In particular, P-MKK6/P-MKK3 are greater activated in case of Itfg1 knockdown compared to control (FIG. 36B). According to STRING database, all indicated proteins are interacting and are linked to cell growth and proliferation (FIG. 36C).
Modified siRNA-GalNAC conjugates were generated to target Itfg1 (FIG. 37A, Table 11; SEQ ID NOs: 7095 and 7096). Western blot analysis with 6 μM and 11 μM, respectively, shows efficient knockdown of Itfg1 by two different conjugates GalNAC-si Itfg1.698 and GalNAC-si Itfg1.680 compared to control (FIG. 37B).
Mfap4 or Itfg1 Knockdown in Mouse Lung Cell Line and Mouse Myoblast Cell Line
Stable cell lines using mouse lung cell line CCL206 and mouse myoblast cell line CRL1722 were generated expressing the respective shRNA—shMfap4, shltfg1 or control shNC (FIG. 38A). Knockdown of Mfap4 as well as the knockdown of Itfg1 accelerates wound healing of mouse lung cells as well as of mouse myoblast cells. These results suggest that Mfap4 and Itfg1 knockdown enhances proliferation and regeneration not only of liver but also of lung and myoblasts.

Example 3—Emulsion +500 Screen and Target Validation

Independent of the TAA chronic damage-induced screen, a functional genetic screen using a focused shRNA library containing 1780 shRNAs targeting 467 genes was also conducted. These 467 genes are the mouse homologs corresponding to differentially up-regulated genes found in our NAFLD patient cohort (FIG. 19A). The screen was conducted in two diet-based mouse models of NAFLD, the “Western Diet” (WD) model (FIG. 4A-4H) and the Choline deficient L-amino acid defined high fat diet (CDHFD) model (FIGS. 20A and 20B). The CDHFD is a very aggressive and fast model leading to NASH with advanced fibrosis in 8 weeks. In contrast, the WD takes about half a year to reach this stage. Similar to the TAA screen, the shRNA library was delivered to the liver by hydro-dynamic tail vine injection (HDTV). The combination of transposon-based constructs with a sleeping beauty 13 transposase-expressing plasmid leads to the stable integration in about 5 to 10% of hepatocytes. After injection, the respective diet exposure was started until NASH with late fibrosis is reached. After harvesting the liver the genomic DNA is isolated, part of the shRNA expression cassette is amplified and the abundance sequenced by NGS. Enriched shRNAs are identified, which indicates an advantage by these shRNAs in the context of fatty liver disease.
In the CDHFD model the majority of shRNAs were depleted (FIG. 19B). Interestingly, based on normalized shRNA abundance level in a principal component analysis, clear segregation between our CDHFD vs normal chow exposed mice (FIG. 19C) was seen. In-depth differential abundance shRNA analysis was then performed. Six shRNAs/targets for validation (FIG. 19D) were identified based on reliable enrichment in the majority of animals. Importantly, as the library was designed based on relevant human patient data and this is a functional genetic screen, scoring in the screen can already be seen as the first validation step.
ABCC4—ATP Binding Cassette Subfamily C Member 4 (MRP4)
This target is a transporter that mediates the efflux of bile components into the blood. Interestingly in all control diet exposed mice, only a low number of relative reads was detected, whereas a strong enrichment in 3 out of 5 CDHFD mice was seen (FIG. 21A-21B). Furthermore, the expression of this gene increases during disease progression in the human patient cohort (FIG. 21C-21E). The expression also significantly increases in relation to the inflammation, fibrosis and ballooning score.
PAK3—P21 (RAC1) Activated Kinase 3
This target is a serine-threonine kinase. In 4 out of 5 mice enrichment for the shRNA targeting PAK3 (FIG. 22A-B; SEQ ID NO: 9) was seen. The expression of PAK3 is significantly upregulated in cirrhosis and fibrosis score 4 NAFLD patients (FIG. 22C-22E). As liver and pancreas both derive from the foregut endoderm during development, it is interesting that Pak 3 was described as a regulator of beta-cell differentiation. In that context, Pak3 promotes cell cycle exit and therefore would have an anti-proliferative function. Therefore, this is a highly interesting target for liver disease and regeneration, too, as confirmed by stable knockdown of Pak3 in the AML12 adult hepatocyte cell line, which accelerates wound healing (FIG. 39 ).
TRNP1—TMF1 Regulated Nuclear Protein 1
This target is a DNA-binding factor with a crucial role in brain development and accelerates cell-cycle progression. So far, no liver related function is described. In control fed mice, a consistent selection against shTrnp1 expressing cells (low relative reads) was detected. However, 4 out of 5 mice on CDHFD show enrichment for shTrnp1 (FIG. 23A-23B; SEQ ID NO: 13). Our human NAFLD patient cohort shows a complicated gene expression pattern of Trnp1 in the liver. In the earlier disease stages, we see a downregulation, but upregulation at the cirrhosis stage (FIG. 23C-23E). Consistent with this during steatosis we see a progressive downregulation.
APLN—Apelin
This target encodes a peptide that functions as an endogenous ligand for the G-protein coupled apelin receptor. In 3 out of 5 CDHFD mice, a strong enrichment for the shRNA targeting Apln compared to the control (FIG. 24A-24B; SEQ ID NO: 11) was seen. Based on the NAFLD patient cohort a significant upregulation at the cirrhosis stage is seen and consistent with this at a fibrotic score of 4 (FIG. 24C-24E). There is already a publication suggesting that Apln promotes hepatic fibrosis through ERK signaling. Also, Apln was described to be different in NAFLD patients and fatty liver rats and suggested as a diagnostic marker. Importantly, the encoded protein is processed into active peptide fragments, making it difficult to be targeted by classic drug approaches and ideal for RNAi based therapeutics.
KIF20A—Kinesin Family Member 20A
This target encodes a mitotic kinesin required for cytokinesis. In 3 out of 5 CDHFD mice, a strong enrichment for the shRNA targeting Kif20a compared to the control (FIG. 25A-25B; SEQ ID NO: 12) is seen. Based on the NAFLD patient cohort data, expression of Kif20a is increasing during disease progression (FIG. 25C-25E). Furthermore, high expression of Kif20a is associated with poor survival in case of HCC. Interestingly, Kif20a-knockdown affects cytokinesis leading to higher polyploidy. Higher polyploidy is also seen in many chronic liver diseases.
LTB—Lymphotoxin Beta
This target encodes a type II membrane protein of the TNF family. In 4 out of 5 CDHFD mice a strong enrichment for the shRNA targeting LTB compared to the control is seen (FIG. 26A-26B; SEQ ID NO: 10). Based on the NAFLD patient cohort data expression of LTB is consistently increasing during disease progression, except at the cirrhosis stage (FIG. 26C-26E). A significant expression increase based on steatosis, inflammation, ballooning and fibrosis score is also seen. Interestingly, LTB was found to regulate liver regeneration, is linked to obesity and animals lacking the lymphotoxin pathway were shown to resist diet-induced obesity.
In addition, a functional genetic screen targeting the top down-regulated genes based on the NAFLD patient cohort is under the way. Also, a functional genomic screen is on the finishing line. In this set up, the inventors screen genome wide (32 shRNA pools of around 2500 to 3000 shRNAs in mice) specifically for modulators of NAFLD disease progression, by only inducing shRNA expression after steatosis is reached before progression to NASH (FIG. 27 ).
List of siRNA Guide Strands:
The siRNA guide strand is identical to the anti-sense strand of the sense-loop-anti-sense RNA structure. This sequence equals the reverse complement sequence of the targeting sequence in the mRNA. The list shows the 21 bp siRNA guide strand. SEQ ID NOs: 15 and 19 were used in the Examples. Light grey marked, bold and underlined are siRNA guide strands with top-DSIR prediction score and predicted by the genomewide sensor prediction algorithm (SEQ ID NOs: 349-351, 457, 465, 468, 470, 473, 1483, 1485, 1486, 1488-1490, 2209, 2225, 2234, 5061, 5062, 5390-5993, 5967, 5970, 5971, 6977, 6978 and 6993).
Sequence Identity
Pairwise and multiple sequence alignment for the purposes of determining percent identity between two or more amino acid or nucleic acid sequences can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalOmega (Söding, J. 2005, Bioinformatics 21, 951-960), T-coffee (Notredame et al. 2000, J. Mol. Biol. (2000) 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298)) and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4) 772-780) software. When using such software, the default parameters, e.g. for gap penalty and extension penalty, are preferably used.
Tables

TABLE 1

Mouse (mus musculus):

SEQ ID		siRNA guide strand/AS
NO	siRNA_id	Sequence

1	Mfap4.1356	UUCAGAGUUGAGCAGUAGCCG

2	Mfap4.760	UUGAGGGAGUAAUAGAAGCCU

3	Grhpr.361	UUCUGCAGUGGCAUCUGUCAG

4	Grhpr.1024	UACAGCUUGAGUUCGCUGGGC

5	Grhpr.1025	UUACAGCUUGAGUUCGCUGGG

6	Iftg1.698	UUAGAGGCAGUCAAUGUCGUG

7	Itfg1.680	UUGAAGUCCAUAAUCAGUGGU

8	Abcc4	UCGAAUUUGUUCACGUCGUUG

9	Pak3	UGUGUAAACAGUUCCUGAUGC

10	Ltb	UCUGGUGUAGAAUCCGCAGCU

11	Apin	UCAAGGAGAGCCAGAGCAGCA

12	Kif20a	UAAUUGACUUGUUUCAUCUAG

13	Trnpl	UGACUUAGUGGGGGUCGGAGU

Human (Homo Sapiens):

TABLE 2

Results for MFAP4. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_	siRNA guide strand/
NO	id	AS Sequence

14	1	AUAGAUGUCGUCACAGUCCAG

15	2	UAUUAUGUUAUUAUUACACUG

16	3	UUGUAGUCAUUCCAGCCGCGG

17	4	UUAUUGAGACCUUCAGUCCCU

18	5	UAGAACCAUGUGCCUCUCGGA

19	6	UAUUGAGACCUUCAGUCCCUA

20	7	UCACACUGCACUGCUCAGCUU

21	8	UUCUGCACCUGACUCCAGGUG

22	9	UCGAAGGUAGAGAACUUCUGG

23	10	UCAGCUUAGCACACUAGGGUG

24	11	UAGGACACCAUCAGCAGGGGA

25	12	UUUAUUGAGACCUUCAGUCCC

26	13	UUGGAGGCAACUCAUUCUCAU

27	14	UAUGUUAUUAUUACACUGUCU

28	15	UCGCAGCUCAUACUUCUGCUU

29	16	UAGAUGUCGUCACAGUCCAGG

30	17	UUAUGUUAUUAUUACACUGUC

31	18	UUGGUGCUCGGGAAUCAGCAG

32	19	UAAACCUCUCAACACCCAGAG

33	20	UAGUAGAAGCCCUUCCACUGG

34	21	UGUAAGGAGUUGGUGCUCGGG

35	22	AUCAGCAGAAGCAUGCAUCAG

36	23	UGUUAUUAUUACACUGUCUUU

37	24	UUCAUUCAGGUUCUGAAGGUU

38	25	UUCUGCACAAAGAGGUCCUGG

39	26	UCUCCAGAGCAUCUCCUCGGA

40	27	UUUGAGAGCAGCCCAGAGGAG

41	28	UUGAGGGAGUAGUAGAAGCCC

42	29	UAUGAUAGUGAGGUGGGCUGG

43	30	UAGAAUACACCAUGGGCCCUG

44	31	UGUAACUUCAGGUGUAGGGGA

45	32	UUGUAAGGAGUUGGUGCUCGG

46	33	UUGUUCUCAAAGUCCUCCAAG

47	34	UGAGGGAGUAGUAGAAGCCCU

48	35	UUCUGCUUCAGUGUCAGGAGG

49	36	AUACUUCUGCUUCAGUGUCAG

50	37	UUAUUAUUACACUGUCUUUUU

51	38	AUGUCGUCACAGUCCAGGGGU

52	39	AUGUUAUUAUUACACUGUCUU

53	40	UCUGCGCUGACCGCGUUCGGG

54	41	UUCCACGGUACUCACCACAGG

55	42	AAGGUUUAUUGAGACCUUCAG

56	43	UAAGGAGUUGGUGCUCGGGAA

57	44	UGUCAGGAGGUGCAUGUUCUG

58	45	AUUAUGUUAUUAUUACACUGU

59	46	UCCUCCUCUGCGCUGACCGCG

60	47	UGAAGGUUUAUUGAGACCUUC

61	48	AAGAUGGACCACAAAGGCCUG

62	49	UUCAGUGUCAGGAGGUGCAUG

63	50	UAGAUGAGGUACACGCCGUCU

64	51	UCAUACUUCUGCUUCAGUGUC

65	52	UUAGGAAUGGAUGCCCUGGGU

66	53	AUGGAGACCAUGGGUGUCCAG

67	54	UACUUCUGCUUCAGUGUCAGG

68	55	UUCAUGCUGUCAGUUCUGCUC

69	56	AAGCAGGACAAGAUGGACCAC

70	57	AUUCUCAUGGAGCCCAGCCAG

71	58	UGCGGAACCAGAAGGCUCCUG

72	59	AGAGAUUGUCCUCUGCUCCCU

73	60	AAGUCCUCCAAGUCCACUCGC

74	61	UCCAAGUCCACUCGCAGCUCA

75	62	UUCAGUCCCUACCCACUCCCA

76	63	UGUUCACACUGCACUGCUCAG

77	64	UAGGAAUGGAUGCCCUGGGUG

78	65	AACCUCUCAACACCCAGAGGG

79	66	UGGGCAUAGAUGUCGUCACAG

80	67	UGGGACAUGGUUUGAGAGCAG

81	68	UCCACGGUACUCACCACAGGG

82	69	AAGACCUCAUAUGCAUGCCUA

83	70	AGCUUGUAGUCAUUCCAGCCG

84	71	UCAUGCUGUCAGUUCUGCUCA

85	72	UGUUGGGACAGGUUGGAGGCA

86	73	AAGCUGAGUAUGAUAGUGAGG

87	74	UGUUGUUCUCAAAGUCCUCCA

88	75	UCUGCUUCAGUGUCAGGAGGU

89	76	UGUUUCAGGGUGGUGUGCGGU

90	77	UGUGCCUCUCGGAAGAGGCCU

91	78	UGUAGUCAUUCCAGCCGCGGA

92	79	UAUUAUUAUUAUGUUAUUAUU

93	80	UAUUAUUAUGUUAUUAUUACA

94	81	UCAGUCCCUACCCACUCCCAG

95	82	UUAUUAUGUUAUUAUUACACU

96	83	UAGGACAGGGAGUCACCUGCC

97	84	UACUCUCCAUCAGCACGGCCG

98	85	UGAGUAUGAUAGUGAGGUGGG

99	86	AUGGAGAAGUCAGCGUACUUG

100	87	AUGAUAGUGAGGUGGGCUGGG

101	88	UGGUAGGACAGGGAGUCACCU

102	89	UGUCAGUUCUGCUCAGAGUGG

103	90	UCUCAAAGUCCUCCAAGUCCA

104	91	UCUGAAGGUUUAUUGAGACCU

105	92	AUUAUUAUUAUGUUAUUAUUA

106	93	UACACGCCGUCUGACUGGUAG

107	94	UUGUCCUCUGCUCCCUCAUGU

108	95	UGUGAAAUACAAGGUUCCCUU

109	96	UCCUGGUCCCGGUCGAAGGUA

110	97	AGCAGAAGCAUGCAUCAGGGG

111	98	GAUGUCGUCACAGUCCAGGGG

112	99	AUGAGGUACACGCCGUCUGAC

113	100	UUUCAGGGUGGUGUGCGGUAG

114	101	UCCACAGUGAGGAAGCAGGAC

115	102	UUUGAGGGAGUAGUAGAAGCC

116	103	UCGGAUCCCGGAGACCUGGGG

117	104	UUCCCUUCUGCACCUGACUCC

118	105	UGCAGAGAUUGUCCUCUGCUC

119	106	AUCUCAGUGCGUUUGAGGGAG

120	107	UCGGUGGUCAUGUCACAGAAG

121	108	CUGAGUAUGAUAGUGAGGUGG

122	109	UGAAAUACAAGGUUCCCUUCU

123	110	AGGUUCUGAAGGUUUAUUGAG

124	111	UGGUCAUGUCACAGAAGACGG

125	112	UUCCAGCCGCGGAAGAAACUU

126	113	UGAUAGUGAGGUGGGCUGGGG

127	114	CAUGCUGUCAGUUCUGCUCAG

128	115	UCAGCUGUUGGGACAGGUUGG

129	116	ACAUGGUUUGAGAGCAGCCCA

130	117	UAAGUUGGUGGGAGGGAUGCU

131	118	CAAGGUUCCCUUCUGCACCUG

132	119	CUCAGCUUAGCACACUAGGGU

133	120	AGAGCAUCUCCUCGGAUCCCG

134	121	UCCUCGGAUCCCGGAGACCUG

135	122	CAUAGAUGUCGUCACAGUCCA

136	123	AACCAGAAGGCUCCUGAGGAG

137	124	CUUGUAGUCAUUCCAGCCGCG

138	125	AGGCCUGUGAAAUACAAGGUU

139	126	UCCCUUCUGCACCUGACUCCA

140	127	UGUGGUAGGACAGGGAGUCAC

141	128	UGAGGAAGCAGGACAAGAUGG

142	129	AGCAUCUCCUCGGAUCCCGGA

143	130	AGAACCAUGUGCCUCUCGGAA

144	131	UGGUGCUCGGGAAUCAGCAGA

145	132	GUUCUGCACAAAGAGGUCCUG

146	133	GUCGAAGGUAGAGAACUUCUG

147	134	AGGUACACGCCGUCUGACUGG

148	135	AACUCAUUCUCAUGGAGCCCA

149	136	AUGCUGAAGAUGGGACAUGGU

150	137	UGCUGAAGAUGGGACAUGGUU

151	138	UGCGCAGUUCUGCACAAAGAG

152	139	UAGCCCUGGGCAUAGAUGUCG

153	140	AAGACGGGCACAGGCACACUG

154	141	AUGCUGUCAGUUCUGCUCAGA

155	142	AAAGUCCUCCAAGUCCACUCG

156	143	AGUAGAAGCCCUUCCACUGGG

157	144	UGUCCUCUGCUCCCUCAUGUG

158	145	UCCACUCGCAGCUCAUACUUC

159	146	UCGGGAAUCAGCAGAAGCAUG

160	147	AUCAGCACGGCCGAAGCCCAG

161	148	GUUAUUAUUACACUGUCUUUU

162	149	UGCGCUGACCGCGUUCGGGGA

163	150	ACAAAGAGGUCCUGGUCCCGG

164	151	AAGUUGGUGGGAGGGAUGCUG

165	152	UGCACCUGACUCCAGGUGUAA

166	153	UGCACUGCUCAGCUUAGCACA

167	154	AGUCCUCCAAGUCCACUCGCA

168	155	UUCACACUGCACUGCUCAGCU

169	156	UCAUAUGCAUGCCUACCUUGG

170	157	UGAGGAGAGAGCUGCGCAGUU

171	158	CAGCUCAUACUUCUGCUUCAG

172	159	UGUCACAGAAGACGGGCACAG

173	160	AAACCUCUCAACACCCAGAGG

174	161	UCUGCACCUGACUCCAGGUGU

175	162	ACAGUGAGGAAGCAGGACAAG

176	163	UGGUUUGAGAGCAGCCCAGAG

177	164	UCUGACUGGUAGCCCUGGGCA

178	165	UCAUCUCAGUGCGUUUGAGGG

179	166	UGAAGAUGGGACAUGGUUUGA

180	167	CAGCUUAGCACACUAGGGUGG

181	168	UCUGCACAAAGAGGUCCUGGU

182	169	UGCCUCUCGGAAGAGGCCUGG

183	170	UGCUCAGCUUAGCACACUAGG

184	171	ACUUCUGCUUCAGUGUCAGGA

185	172	AUUAUUAUGUUAUUAUUACAC

186	173	UCAUGUCACAGAAGACGGGCA

187	174	AGAUGAGGUACACGCCGUCUG

188	175	GUUGUUCUCAAAGUCCUCCAA

189	176	UCAACACCCAGAGGGUAUGGG

190	177	AUUCAGGUUCUGAAGGUUUAU

191	178	CUGAAGGUUUAUUGAGACCUU

192	179	UGGAGAGAAGCAGCAGCAGCG

193	180	UCAAAGUCCUCCAAGUCCACU

194	181	UUGAGAGCAGCCCAGAGGAGU

195	182	UUGGUGGGAGGGAUGCUGAAG

196	183	UAGUCAUUCCAGCCGCGGAAG

197	184	AUGGACCACAAAGGCCUGCAG

198	185	AAUACAAGGUUCCCUUCUGCA

199	186	CAUGGUUUGAGAGCAGCCCAG

200	187	UCAUUCAGGUUCUGAAGGUUU

201	188	UUAUUAUUAUGUUAUUAUUAC

202	189	AGGCAACUCAUUCUCAUGGAG

203	190	UGGAGAAGUCAGCGUACUUGG

204	191	AGUACUCUCCAUCAGCACGGC

205	192	AUACAAGGUUCCCUUCUGCAC

206	193	ACUGCUCAGCUUAGCACACUA

207	194	CUAGAAUACACCAUGGGCCCU

208	195	UCAGCAGAAGCAUGCAUCAGG

209	196	UCCUGAGGAGAGAGCUGCGCA

210	197	AUCCUCCUCUGCGCUGACCGC

211	198	CUCCAGAGCAUCUCCUCGGAU

212	199	AGUGCCUUCAUGCUGUCAGUU

213	200	CACACUGCACUGCUCAGCUUA

214	201	CUCUCCAGAGCAUCUCCUCGG

215	202	AAAUACAAGGUUCCCUUCUGC

216	203	UGGAGGCAACUCAUUCUCAUG

217	204	UUCAGGUUCUGAAGGUUUAUU

218	205	CUGCUCAGCUUAGCACACUAG

219	206	CACAAAGAGGUCCUGGUCCCG

220	207	UACACCAUGGGCCCUGUUCAC

221	208	UCAGGAGGUGCAUGUUCUGCA

222	209	UGUCAGCUGUUGGGACAGGUU

223	210	AGCAGAGGGAGCACUCAUGGA

224	211	GAGACCUUCAGUCCCUACCCA

225	212	ACUCGCAGCUCAUACUUCUGC

226	213	ACUCAUUCUCAUGGAGCCCAG

227	214	UGGUCCCGGUCGAAGGUAGAG

228	215	CUGUGAAAUACAAGGUUCCCU

229	216	UACCCACUCCCAGCCCUGCAG

230	217	UUCUCAAAGUCCUCCAAGUCC

231	218	AGCCGCGGAAGAAACUUACUG

232	219	AGAUGUCGUCACAGUCCAGGG

233	220	AGCACUCAUGGAGACCAUGGG

234	221	ACUCUCCAUCAGCACGGCCGA

235	222	CUUCAGUGUCAGGAGGUGCAU

236	223	GAAGCUGAGUAUGAUAGUGAG

237	224	CAGGAGGUGCAUGUUCUGCAG

238	225	CAUCUCAGUGCGUUUGAGGGA

239	226	AGUGUAACUUCAGGUGUAGGG

240	227	ACAAGGUUCCCUUCUGCACCU

241	228	AGGUUUAUUGAGACCUUCAGU

242	229	CUCCUCUGCGCUGACCGCGUU

243	230	AUUGUCCUCUGCUCCCUCAUG

244	231	CACUCGCAGCUCAUACUUCUG

245	232	UCCACUUCCCGCCCUCGGUGG

246	233	CAGGCUAGAACCAUGUGCCUC

247	234	AAAGAGGUCCUGGUCCCGGUC

248	235	CUCGGGAAUCAGCAGAAGCAU

249	236	ACGGGCACAGGCACACUGGGG

250	237	CUCUCCAUCAGCACGGCCGAA

251	238	UCAGGUUCUGAAGGUUUAUUG

252	239	AGUUCUGCACAAAGAGGUCCU

253	240	UAGAAGCCCUUCCACUGGGCC

254	241	AGUAUGAUAGUGAGGUGGGCU

255	242	ACAGGUUGGAGGCAACUCAUU

256	243	ACCAUGUGCCUCUCGGAAGAG

257	244	AGCUGUUGGGACAGGUUGGAG

258	245	ACCUCUCCAGAGCAUCUCCUC

259	246	UCCUCUGCGCUGACCGCGUUC

260	247	GGUCAUGUCACAGAAGACGGG

261	248	AUGGUUUGAGAGCAGCCCAGA

262	249	UCAGGGUGGUGUGCGGUAGCU

263	250	UACAAGGUUCCCUUCUGCACC

264	251	AAGAGGUCCUGGUCCCGGUCG

265	252	UCCAGCCGCGGAAGAAACUUA

266	253	CUCAUAUGCAUGCCUACCUUG

267	254	AAGGUUCCCUUCUGCACCUGA

268	255	UGCUGUCAGUUCUGCUCAGAG

269	256	AACACCCAGAGGGUAUGGGGA

270	257	GUAGAUGAGGUACACGCCGUC

271	258	UAGGCCGUGUUGUUCUCAAAG

272	259	AGAUGGGACAUGGUUUGAGAG

273	260	UUCCACUGGGCCCAGUUGAUG

274	261	CAGCUGUUGGGACAGGUUGGA

275	262	AGCCCUGCAGAGAUUGUCCUC

276	263	CAUACUUCUGCUUCAGUGUCA

277	264	UUCUGAAGGUUUAUUGAGACC

278	265	AGGACAGGGAGUCACCUGCCC

279	266	ACAAGAUGGACCACAAAGGCC

280	267	AGAGGUCCUGGUCCCGGUCGA

281	268	AGCUGAGUAUGAUAGUGAGGU

282	269	UCCCUACCCACUCCCAGCCCU

283	270	AGGCUCCUGAGGAGAGAGCUG

284	271	AGACCAUGGGUGUCCAGGGGA

285	272	GUCCACUCGCAGCUCAUACUU

286	273	AUUGAGACCUUCAGUCCCUAC

287	274	AUGAGGCCUGUGAAAUACAAG

288	275	UCACAGAAGACGGGCACAGGC

289	276	AGAUUGUCCUCUGCUCCCUCA

290	277	AGACCUUCAGUCCCUACCCAC

291	278	CUGUUCACACUGCACUGCUCA

292	279	GUAGGACACCAUCAGCAGGGG

293	280	GUGUAACUUCAGGUGUAGGGG

294	281	GAGACCAUGGGUGUCCAGGGG

295	282	CAACUCAUUCUCAUGGAGCCC

296	283	CUGACUGGUAGCCCUGGGCAU

297	284	GGAAGAAACUUACUGAGCCAU

298	285	CGGAAGAAACUUACUGAGCCA

299	286	CUGUCAGUUCUGCUCAGAGUG

300	287	CCCAGCUUGUAGUCAUUCCAG

301	288	AAGCCCUUCCACUGGGCCCAG

302	289	GUACACGCCGUCUGACUGGUA

303	290	GCUAAACCUCUCAACACCCAG

304	291	AGAAGCAGCAGCAGCGGCAGG

305	292	UCAGUGUCAGGAGGUGCAUGU

306	293	AGAGAAGCAGCAGCAGCGGCA

307	294	UGACUGGUAGCCCUGGGCAUA

308	295	CUGCUUCAGUGUCAGGAGGUG

309	296	CACGGUACUCACCACAGGGGA

310	297	CUCGGUGGUCAUGUCACAGAA

311	298	AAGGAGUUGGUGCUCGGGAAU

312	299	GAGUAUGAUAGUGAGGUGGGC

313	300	GGAAUCAGCAGAAGCAUGCAU

314	301	CUAGAACCAUGUGCCUCUCGG

315	302	CUCGCAGCUCAUACUUCUGCU

316	303	UGCUUCAGUGUCAGGAGGUGC

317	304	UCCUCCAAGUCCACUCGCAGC

318	305	AGGAGUGCCUUCAUGCUGUCA

319	306	GUCCUCCAAGUCCACUCGCAG

320	307	ACACUGCACUGCUCAGCUUAG

321	308	GAGUAGUAGAAGCCCUUCCAC

322	309	GUAGUCAUUCCAGCCGCGGAA

323	310	CUGCAGAGAUUGUCCUCUGCU

324	311	AUGGGCCCUGUUCACACUGCA

325	312	AUAGGCCGUGUUGUUCUCAAA

326	313	AUGGGACAUGGUUUGAGAGCA

327	314	GAGGGAGUAGUAGAAGCCCUU

328	315	GACAGGUUGGAGGCAACUCAU

329	316	CCUCAUAUGCAUGCCUACCUU

330	317	AAUCAGCAGAAGCAUGCAUCA

331	318	CCAGGCUAGAACCAUGUGCCU

332	319	UGCACAAAGAGGUCCUGGUCC

333	320	CGUGGAGAGAAGCAGCAGCAG

334	321	CUGCACCUGACUCCAGGUGUA

335	322	CUCCAAGUCCACUCGCAGCUC

336	323	AGUAGUAGAAGCCCUUCCACU

337	324	UCAGUGCGUUUGAGGGAGUAG

338	325	GGUAGGACAGGGAGUCACCUG

339	326	CAGGGUGGUGUGCGGUAGCUG

340	327	AGACGGGCACAGGCACACUGG

341	328	CACAGUGAGGAAGCAGGACAA

342	329	CUUCAUGCUGUCAGUUCUGCU

343	330	GGAGAGAAGCAGCAGCAGCGG

344	331	UGAGGUACACGCCGUCUGACU

345	332	CUCCUGAGGAGAGAGCUGCGC

346	333	AUCUCCUCGGAUCCCGGAGAC

347	334	UGAGACCUUCAGUCCCUACCC

TABLE 3

Results for GRHPR. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID		siRNA guide strand/AS
NO	siRNA_id	Sequence

348	1	UUCUGGGCUCGUCACAUCCAG

349	2	UGAUGUUGAUGAACACAGCUG

350	3	AUGUUGAUGAACACAGCUGUU

351	4	UAGACACAAACUCUGCCUGGA

352	5	UUCUGGAAGAAGUCCUUGUUG

353	6	UUGUUGCAGAGUCCCUCGGUU

354	7	UCACAUCCAGUCCAGCAGCUG

355	8	AUCUUCUGGAAGAAGUCCUUG

356	9	UGGAAGAAGUCCUUGUUGCAG

357	10	UUUGUAGGCAGUGGUUCUGGG

358	11	UGUUGAUGAACACAGCUGUUU

359	12	AAUCUCUGGACACCGAAUGGU

360	13	UUCUGCUGCUUCCUCAGGCCU

361	14	UACAGAAAUCUCUGGACACCG

362	15	UCGUCACAUCCAGUCCAGCAG

363	16	UUGAUGAACACAGCUGUUUCC

364	17	UUGCAGAGUCCCUCGGUUGCA

365	18	UGAUGAACACAGCUGUUUCCU

366	19	UCAUCUUCUGGAAGAAGUCCU

367	20	UCUGCUGCUUCCUCAGGCCUG

368	21	UCGGUUGCAGGUGUUAAGGAG

369	22	UUGUAGGCAGUGGUUCUGGGC

370	23	UUCCUUCAUCUUCUGGAAGAA

371	24	UCUGCCUGGAAUUCUGCUGCU

372	25	UUCUUCAGGGUCAGGAGAGGG

373	26	UGGAAUUCUGCUGCUUCCUCA

374	27	AGCUGUUUCCUUCAUCUUCUG

375	28	UGUUUCCUUCAUCUUCUGGAA

376	29	UUCAUCUUCUGGAAGAAGUCC

377	30	AUGAACACAGCUGUUUCCUUC

378	31	ACAGAAAUCUCUGGACACCGA

379	32	UUGCAGGUGUUAAGGAGCAGG

380	33	UCUCUGGACACCGAAUGGUUU

381	34	UCUUCUGGAAGAAGUCCUUGU

382	35	UGGUACAGGUCGUCCUGGUUU

383	36	CUGAUGUUGAUGAACACAGCU

384	37	GUAGACACAAACUCUGCCUGG

385	38	AUGGUUUCAGACGCCGAGCAA

386	39	AACUCUGCCUGGAAUUCUGCU

387	40	AUCUCUGGACACCGAAUGGUU

388	41	UAGGCAGUGGUUCUGGGCUCG

389	42	UGUACAGAAAUCUCUGGACAC

390	43	UGUUGCAGAGUCCCUCGGUUG

391	44	UGCUGAUGUUGAUGAACACAG

392	45	UUCAGGGUCAGGAGAGGGUGG

393	46	CUUGUUGCAGAGUCCCUCGGU

394	47	ACUCUGCCUGGAAUUCUGCUG

395	48	CAGAAAUCUCUGGACACCGAA

396	49	UGAAAUCAGAUUGGGCAGCCA

397	50	CAUCUUCUGGAAGAAGUCCUU

398	51	UGCAGAGUCCCUCGGUUGCAG

399	52	AGUCCUUGUUGCAGAGUCCCU

400	53	AAGUCCUUGUUGCAGAGUCCC

401	54	UCCUGGUUUACGACGUCGCCC

402	55	GAUGUUGAUGAACACAGCUGU

403	56	AAAUCUCUGGACACCGAAUGG

404	57	UCAGGGUCAGGAGAGGGUGGU

405	58	UUUCCUUCAUCUUCUGGAAGA

406	59	AAGAAGUCCUUGUUGCAGAGU

407	60	CUGCCUGGAAUUCUGCUGCUU

408	61	UCGUCCUGGUUUACGACGUCG

409	62	UGAACACAGCUGUUUCCUUCA

410	63	GAACACAGCUGUUUCCUUCAU

411	64	CAGUCCAGCAGCUGCAAUCUU

412	65	ACAUCCAGUCCAGCAGCUGCA

413	66	UCCUUGUUGCAGAGUCCCUCG

414	67	AGACACAAACUCUGCCUGGAA

415	68	AGUCCAGCAGCUGCAAUCUUA

416	69	AAUUCUGCUGCUUCCUCAGGC

417	70	UGCUGCUUCCUCAGGCCUGGG

418	71	ACAGCUGUUUCCUUCAUCUUC

419	72	CUUCUGGAAGAAGUCCUUGUU

420	73	AAACUCUGCCUGGAAUUCUGC

421	74	CACAGCUGUUUCCUUCAUCUU

422	75	UCUGGGCUCGUCACAUCCAGU

423	76	AUCCAGUCCAGCAGCUGCAAU

424	77	AGCAGCUGCAAUCUUACCACU

425	78	UGCUUCCUCAGGCCUGGGCUG

426	79	UGUAGGCAGUGGUUCUGGGCU

427	80	UACAGGUCGUCCUGGUUUACG

428	81	CAUCCAGUCCAGCAGCUGCAA

429	82	AGAGUCCCUCGGUUGCAGGUG

430	83	UCUUCAGGGUCAGGAGAGGGU

431	84	UCCUUCAUCUUCUGGAAGAAG

432	85	CCUUGUUGCAGAGUCCCUCGG

433	86	AACACAGCUGUUUCCUUCAUC

434	87	AGUCCCUCGGUUGCAGGUGUU

435	88	GUUGCAGGUGUUAAGGAGCAG

436	89	UCUGGAAGAAGUCCUUGUUGC

437	90	GAUGAACACAGCUGUUUCCUU

438	91	CUGGUUUACGACGUCGCCCCU

439	92	CUGGUACAGGUCGUCCUGGUU

440	93	CUGUUUCCUUCAUCUUCUGGA

441	94	AGGCCUGGUACAGGUCGUCCU

442	95	ACGACGAUGAAAUCAGAUUGG

443	96	AUUCUGCUGCUUCCUCAGGCC

444	97	CAGCUGCAAUCUUACCACUGG

445	98	GCAGCUGCAAUCUUACCACUG

446	99	AGUUCUUCAGGGUCAGGAGAG

447	100	ACCGAAUGGUUUCAGACGCCG

448	101	ACAGUUCUUCAGGGUCAGGAG

449	102	GUCCUUGUUGCAGAGUCCCUC

450	103	GCUGUUUCCUUCAUCUUCUGG

451	104	AAUGGUUUCAGACGCCGAGCA

452	105	UCUGGACACCGAAUGGUUUCA

453	106	ACAAACUCUGCCUGGAAUUCU

454	107	UGGUUUGUAGGCAGUGGUUCU

455	108	CAAACUCUGCCUGGAAUUCUG

456	109	CUGCUGAUGUUGAUGAACACA

TABLE 4

Results for ITFG1. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_	siRNA guide strand/
NO	id	AS Sequence

457	1	UAUAAAUACACAAACACUGGA

458	2	UAGAUCACCAUUGAAAUCCAU

459	3	UAGAAUAAGAAGCAAGACCAA

460	4	UUGCAUUGAAGUCUGAAUGUA

461	5	UUGACCACUUACUCUGUGCUA

462	6	UUAAUGUUUACAGUAACUCAA

463	7	UAUACAUGAUAUAAGGUCCAG

464	8	UUAUCUUACGAGGACAGUCAU

465	9	UUAUAAAUACACAAACACUGG

466	10	UUUAGGUCUGUCAGCUCCCAG

467	11	UAUCAAUGCACUGUGAUUCUU

468	12	UAUUGCUGAAAUCUUGUAGGA

469	13	AUAUUGACCACUUACUCUGUG

470	14	UACUUGUAGUGGUCAAUGCUG

471	15	UUACUCUGUGCUAGGCACCAA

472	16	AUUUAUUUGAAUACUUUCCAA

473	17	UAUGGAAUGACAAUUAGCUGG

474	18	UAGGACUGGAACCCACUGCUU

475	19	UAAUAUGAGCAAGUAAAUCUU

476	20	UAAGUCUAAUAAGAUCAUCUA

477	21	UUUACUUAGCACUACAAUGUC

478	22	UUAUAGACUUCUCCAAGUGUU

479	23	UGACCUGCUGUGAUGAAGCUG

480	24	AUACUUUCCAAUAAUUACCAU

481	25	UUGCGCUCCGACCUAAACCAA

482	26	UAGACUUUAAACAUUCGACGC

483	27	UUAUUAGCAUUGAUAAACUUU

484	28	UAGAACACAGACCACUAAGAA

485	29	UUCUUUAGUAUGACCAGAGCG

486	30	UAGCACUACAAUGUCCAAGAU

487	31	UUGAGUAUGGUCAUAUUGUUA

488	32	UAUAGCAGUAAGCAGAACAAU

489	33	UGACUGUCCAACCACCAUCAU

490	34	AAUCUUUAUGUCAAUCACCAA

491	35	AUUAUUAGCAUUGAUAAACUU

492	36	UAUUGUAGUCUCCAAUAUGAA

493	37	UUAGUAUGACCAGAGCGUCUG

494	38	AUAAAUACACAAACACUGGAG

495	39	UUGAAUUAGGAGUUUAAGGCA

496	40	UUGUAGGACUGGAACCCACUG

497	41	UAGGAGUUUAAGGCAAGUCUG

498	42	UAUCAGGAAUUAGAUCACCAU

499	43	UCGUCAGGAAUAAAUCUGCUG

500	44	UUGAUUUAGGUCUGUCAGCUC

501	45	UAUUUAUUUGAAUACUUUCCA

502	46	UAUUUCUAUAAUUAGAUGUAU

503	47	UUGUAGUGGUCAAUGCUGGAU

504	48	UGGAAUGACAAUUAGCUGGGA

505	49	UUGUAUAUCCUUUACUUAGCA

506	50	AUUAUAAAUACACAAACACUG

507	51	UAUAGUACUGACAGAGAAGUU

508	52	UAAACAUUCGACGCGCCUCUU

509	53	AUUAAUAAUGACAACUACCAC

510	54	UUGUUAUCAAUGCACUGUGAU

511	55	UAUCAAGUCUAUGUAUUUCUA

512	56	UUGGAGAGCUAAAUGUGCGGA

513	57	UUUCCAAUAAUUACCAUGGGA

514	58	UAUUGUUAGGAUCUAAUGUUU

515	59	UAGUAUGACCAGAGCGUCUGG

516	60	UUAAUAAUGACAACUACCACA

517	61	UAAGGCAAGUCUGUCUUACUG

518	62	AAGUCUAAUAAGAUCAUCUAA

519	63	UAAGCAGAACAAUAUUACUUG

520	64	UUGAAAGAUACCUUUACUUUG

521	65	UACUGUGCUACCAAGUCAGAG

522	66	UAAGCACUUCACAUACAUCAU

523	67	UUUGGAAUGAUUGCAGUCCAC

524	68	UAUAAUUAGAUGUAUAAGUCU

525	69	UAAUUAGAUGUAUAAGUCUAA

526	70	UAAAUUAUAGACUUCUCCAAG

527	71	AUAUGUCAGAAGGACAUCCAU

528	72	UCUUUGUAUAUCCUUUACUUA

529	73	UUGGAGAGUACUAUAAUUUUU

530	74	UUAAUUCUUGGAGAGUACUAU

531	75	AUAAUUAGAUGUAUAAGUCUA

532	76	UAAGAAGCAAGACCAAGUCAA

533	77	UAGGGCACAUUAAUUCUUGGA

534	78	UCUGUCUUACUGUGCUACCAA

535	79	UUCUUUGUAUAUCCUUUACUU

536	80	UUAUAAAUAAUAUUUAAUCUC

537	81	UACAUCAUCCCAUUUAAUGUU

538	82	UUGCAUUAUUACAAGGGACGU

539	83	UAAUAAUGACAACUACCACAU

540	84	UUUGAUUUAGGUCUGUCAGCU

541	85	UUUCAGUUGGUUGCUGUUCAU

542	86	UGAUUCUUGAAAGAUACCUUU

543	87	UUGGUUGCUGUUCAUCCACAA

544	88	UUGCAUUCCCAGAUGCUGCCU

545	89	UAUAUCCUUUACUUAGCACUA

546	90	AAUGAUUGCAGUCCACUCUUG

547	91	UUGUAUACAUGAUAUAAGGUC

548	92	UUCAACUAAUCAAGUGAACAG

549	93	UUAAAGGCAAGUCACAUAGCA

550	94	UUACAGUAACUCAAGUAUUAG

551	95	AAUAUGAGCAAGUAAAUCUUU

552	96	AAUAAUGACAACUACCACAUA

553	97	AUGUCGUCAGGAAUAAAUCUG

554	98	UAUCUUACGAGGACAGUCAUU

555	99	UUACUUAGCACUACAAUGUCC

556	100	AUUUAGGUCUGUCAGCUCCCA

557	101	UUUAUUUGAAUACUUUCCAAU

558	102	UCGAGGGACAUUGUGAGGGUA

559	103	UUCCAUCUUCGUAAAUGUCAA

560	104	AAGAAUAUUUCUUCAUGCCUG

561	105	AUCUUGUAGGACUGGAACCCA

562	106	UACUUAGCACUACAAUGUCCA

563	107	UAAUUGGAAUUGGUAUUUCAG

564	108	UUUAAUGUUUACAGUAACUCA

565	109	UUGCUGUUCAUCCACAAAUGG

566	110	UGAAUGCCUAAUGACUCCGUG

567	111	UCAAACUGGAAGGUACUAGUG

568	112	AACAGCUCCUAAUUCACUCUU

569	113	UCCAAUAUAGUACUGACAGAG

570	114	UUCAAGAAAUCAAAUGUUCUU

571	115	UUAAGAAGACAUGUUAACAUG

572	116	UAAAGGCAAGUCACAUAGCAU

573	117	UACACAAACACUGGAGUACAU

574	118	UGAAUUAGGAGUUUAAGGCAA

575	119	AAUUUGAUUUAGGUCUGUCAG

576	120	UUUACAGAGGUUAAACAAGAG

577	121	AAGAACAAUAACUUUAACAAA

578	122	UAAAUAAUAUUUAAUCUCCCC

579	123	AUAUUGUUAGGAUCUAAUGUU

580	124	UAUUUAUUAAGAAGACAUGUU

581	125	UAGAUGUAUAAGUCUAAUAAG

582	126	UAAGUAGAUGGUACUCUUUUG

583	127	AACUAAUCAAGUGAACAGCCA

584	128	UACAUGCAACACAUUCCACAA

585	129	UUUGCAUUGAAGUCUGAAUGU

586	130	UUUGAGAAUAGAAAUGUGAUU

587	131	UAAGUGGUUGAAUUAGGAGUU

588	132	UUUAUUAAGAAGACAUGUUAA

589	133	UUGGAAUUGGUAUUUCAGUUG

590	134	AUCAAGUCUAUGUAUUUCUAU

591	135	UUCAUUAUCACAUGAUAAGGA

592	136	AACAAUGACUUUGUAAGUGGU

593	137	AUUGAGUAUGGUCAUAUUGUU

594	138	UACAGUUGUAUACAUGAUAUA

595	139	UACCAAGUCAGAGUACCCGAU

596	140	UAUAAGUCUAAUAAGAUCAUC

597	141	UGGUAUUUCAGUUGGUUGCUG

598	142	AAGCAGAACAAUAUUACUUGG

599	143	AAAUACACAAACACUGGAGUA

600	144	UGCAUUAUUACAAGGGACGUU

601	145	UUGUAAGUGGUUGAAUUAGGA

602	146	UACUUGGUGUAAGAUACAGUU

603	147	UUAAUUUGAUUUAGGUCUGUC

604	148	AAUAAGAUUAUAAAUACACAA

605	149	UUGGAUUCAUUUGUGAUACCA

606	150	UAAGCAUCUGCUUCAAAGUUA

607	151	AGACUUUAAACAUUCGACGCG

608	152	ACAUAUUGACCACUUACUCUG

609	153	UGACAGAGAAGUUUCCAUCCA

610	154	UAGGUCUGUCAGCUCCCAGUA

611	155	AUCUACAGUUGUAUACAUGAU

612	156	UAUGUAUUUCUAUAAUUAGAU

613	157	ACCACUAAGAACAAUAACUUU

614	158	UGUGAUGAAGCUGAAUGCCUA

615	159	UCAGAUACCCAUUUGCAUCUA

616	160	AUUAGCAUUGAUAAACUUUUU

617	161	UAACAGCUCCUAAUUCACUCU

618	162	AUAAUGACAACUACCACAUAU

619	163	UAUUAAUAAUGACAACUACCA

620	164	UAUUUGAAUACUUUCCAAUAA

621	165	UAAAUGCAUGAGAAUGUGGAA

622	166	UAAUGUUUACAGUAACUCAAG

623	167	UACAGCACUACAGAAUAGAGA

624	168	UUGGUGUAAGAUACAGUUUGG

625	169	AAUGUGAUUGAAGAUUUGCAU

626	170	UGUAAGUGGUUGAAUUAGGAG

627	171	AUUACUUGGUGUAAGAUACAG

628	172	UUUACAGUAACUCAAGUAUUA

629	173	UCGUAAAUGUCAAAGAAGGUG

630	174	UUGGUAUUUCAGUUGGUUGCU

631	175	ACACUUGUUAUCAAUGCACUG

632	176	UUCACAUACAUCAUCCCAUUU

633	177	AACUGGAAGGUACUAGUGGUG

634	178	UAGGAUCUAAUGUUUGAUUUU

635	179	UCUUUAGUAUGACCAGAGCGU

636	180	UUAUGUAAUAUUAAAGGCAAG

637	181	UACUGACAGAGAAGUUUCCAU

638	182	AUGACUUUGUAAGUGGUUGAA

639	183	AUUACAAGGGACGUUCUCCAG

640	184	UCUGUGCUAGGCACCAAGCUA

641	185	UACCCAUUUGCAUCUACAGUU

642	186	UGCAUCUACAGUUGUAUACAU

643	187	UCAUUCUUUGUAUAUCCUUUA

644	188	UUAGAUCACCAUUGAAAUCCA

645	189	UUGAGAAUAGAAAUGUGAUUG

646	190	UAUGUCAGAAGGACAUCCAUU

647	191	UAAGAACAAUAACUUUAACAA

648	192	UUGUGACAUAUUCAAACCAUA

649	193	UUUAGUAUGACCAGAGCGUCU

650	194	UUGUAUGGUAGUUGGAGAGCU

651	195	UUGCAGUCCACUCUUGUUUUC

652	196	UAUUAGCAUUGAUAAACUUUU

653	197	UAGUCUCCAAUAUGAAGGGUA

654	198	UUUCAAACUGGAAGGUACUAG

655	199	AAUUAUAGACUUCUCCAAGUG

656	200	AUAAGCAUCUGCUUCAAAGUU

657	201	AAACUGGAAGGUACUAGUGGU

658	202	AUGACAACUACCACAUAUUGA

659	203	UGUAUUUCUAUAAUUAGAUGU

660	204	AAGUCUGCAAAUGCUGACUGU

661	205	UCUCUAUCAUCUGCUUUCUUU

662	206	ACAACUACCACAUAUUGACCA

663	207	UAUUCAAACCAUAUUUAUUUG

664	208	UUCGUAAAUGUCAAAGAAGGU

665	209	AUUGCUGAAAUCUUGUAGGAC

666	210	UUCGAGGGACAUUGUGAGGGU

667	211	AGUCAUUAGAACACAGACCAC

668	212	UAGACUUCUCCAAGUGUUUGA

669	213	UUAUUGCUGAAAUCUUGUAGG

670	214	ACUAAUCAAGUGAACAGCCAU

671	215	UUGAAGUCUGAAUGUAAAUUA

672	216	AUGAGAAUGUGGAAUUCGCAU

673	217	UGUAAAUUAUAGACUUCUCCA

674	218	UAUAGACUUCUCCAAGUGUUU

675	219	UUAGGAUCUAAUGUUUGAUUU

676	220	UCUUGUAGGACUGGAACCCAC

677	221	UGCUGACUGUCCAACCACCAU

678	222	UUAGAAUAAGAAGCAAGACCA

679	223	UGUUAGGAUCUAAUGUUUGAU

680	224	UGGUCAUAUUGUUAGGAUCUA

681	225	UUGAAUACUUUCCAAUAAUUA

682	226	UGAUUGCAGUCCACUCUUGUU

683	227	UUAAACAUUCGACGCGCCUCU

684	228	AUGUUUACAGUAACUCAAGUA

685	229	UUACUGUGCUACCAAGUCAGA

686	230	UUCUUCAUUAUCACAUGAUAA

687	231	UGAAUGUAAAUUAUAGACUUC

688	232	UAGCUGGGAAUUUGGAAUGAU

689	233	UAGGCAUCACAUGUCCAUUUG

690	234	UGAUAUAAGGUCCAGGUUGAU

691	235	UCUAUGUAUUUCUAUAAUUAG

692	236	UGCAACACAUUCCACAAAGGA

693	237	UUUAAACAUUCGACGCGCCUC

694	238	UUGAAGAUUUGCAUUCCCAGA

695	239	UGUGAUUCUUGAAAGAUACCU

696	240	GUAAAUUAUAGACUUCUCCAA

697	241	AAAUGCUGACUGUCCAACCAC

698	242	UCUUGAAAGAUACCUUUACUU

699	243	UACUUUCCAAUAAUUACCAUG

700	244	AUUGAAGAUUUGCAUUCCCAG

701	245	UGCUGAAAUCUUGUAGGACUG

702	246	AUUCCCUCCUAAUAGUAUCUG

703	247	UGUAGUCUCCAAUAUGAAGGG

704	248	UGUUUCAACUAAUCAAGUGAA

705	249	UAUAAUUUGCAUCAUUAGAAU

706	250	AUUGUUAGGAUCUAAUGUUUG

707	251	AUAUCCUUUACUUAGCACUAC

708	252	UGUAUGGUAGUUGGAGAGCUA

709	253	AACAUGCUUAGAUACAAAGUA

710	254	AUGUUCUUCAUUAUCACAUGA

711	255	UACCCGAUCACUAUAUUGUAU

712	256	UGUUCUUCAUUAUCACAUGAU

713	257	UUAGCUGGGAAUUUGGAAUGA

714	258	UAAAUACACAAACACUGGAGU

715	259	AGGAAUUAGAUCACCAUUGAA

716	260	UUCCCUCCUAAUAGUAUCUGU

717	261	UUACUUGGUGUAAGAUACAGU

718	262	AAAGAUACCUUUACUUUGGGU

719	263	UUAGAUGUAUAAGUCUAAUAA

720	264	ACACAUUCCACAAAGGAACAA

721	265	UCUACAGUUGUAUACAUGAUA

722	266	UGUAUAUCCUUUACUUAGCAC

723	267	UUGUUAGGAUCUAAUGUUUGA

724	268	UCUGCAAAUGCUGACUGUCCA

725	269	UACCAACGUAGAGAUGGUCAA

726	270	UAAACCAAGCACGUUGUAUGG

727	271	AAGAAAUCAAAUGUUCUUCAU

728	272	UCACAUGAUAAGGAUAAGUUU

729	273	UGAAAUCUUGUAGGACUGGAA

730	274	UGUCAGAAGGACAUCCAUUUG

731	275	ACUUAGCACUACAAUGUCCAA

732	276	AACUUCGAGGGACAUUGUGAG

733	277	AUGGAAUGACAAUUAGCUGGG

734	278	AUAUUUAUUAAGAAGACAUGU

735	279	UACCAUGGGAUACAUCAUUUA

736	280	AUCUUCGUAAAUGUCAAAGAA

737	281	UCUUACUGUGCUACCAAGUCA

738	282	UCAUUAUCACAUGAUAAGGAU

739	283	UAAUUUGAUUUAGGUCUGUCA

740	284	AGUACAUGCAACACAUUCCAC

741	285	AUCAUUCUUUGUAUAUCCUUU

742	286	AAAUAAUAUUUAAUCUCCCCU

743	287	CAAGUCUGUCUUACUGUGCUA

744	288	AAAGUCUGCAAAUGCUGACUG

745	289	AUGAUUGCAGUCCACUCUUGU

746	290	AAACCAAGCACGUUGUAUGGU

747	291	AUAAAUAAUAUUUAAUCUCCC

748	292	UUUGCAUCAUUAGAAUAAGAA

749	293	AACACAGACCACUAAGAACAA

750	294	ACAAUGACUUUGUAAGUGGUU

751	295	UUCUAUAAUUAGAUGUAUAAG

752	296	AUUUAUUAAGAAGACAUGUUA

753	297	AUUGAAAUCCAUAAUUAGUGG

754	298	AUUAUAGACUUCUCCAAGUGU

755	299	AAUGACAACUACCACAUAUUG

756	300	AAGUGGUUGAAUUAGGAGUUU

757	301	AUAGUACUGACAGAGAAGUUU

758	302	AAAGAAUAUUUCUUCAUGCCU

759	303	UCCAUCUCCAUCAAAGUCUGC

760	304	UGACAUAUUCAAACCAUAUUU

761	305	UAGCAGUAAGCAGAACAAUAU

762	306	UGACCACUUACUCUGUGCUAG

763	307	AUAAGGUCCAGGUUGAUUCAC

764	308	UAUAGGCAUCACAUGUCCAUU

765	309	UGUUUGAGAAUAGAAAUGUGA

766	310	AUAGACUUCUCCAAGUGUUUG

767	311	UGUCCAAGAUUCCAUCUUCGU

768	312	UUCUAUCAAGUCUAUGUAUUU

769	313	AGAAGACAUGUUAACAUGCUU

770	314	AUGUACAGCACUACAGAAUAG

771	315	UAGGCACCAAGCUAAGCACUU

772	316	UCAUUAGAACACAGACCACUA

773	317	UCAUUUAUAAAUAAUAUUUAA

774	318	AGAAUCUCCAUCAUAAUCCCC

775	319	UAAUUCUUGGAGAGUACUAUA

776	320	AUCUCAGUGAACUAUAAAGAA

777	321	AUCCUUUACUUAGCACUACAA

778	322	AUGUCCAUUUGCAUACUAGAA

779	323	UAAAUCUUUAUGUCAAUCACC

780	324	UCCAUCUUCGUAAAUGUCAAA

781	325	UUUAAGGCAAGUCUGUCUUAC

782	326	ACUAAGUAGAUGGUACUCUUU

783	327	AUGCUGACUGUCCAACCACCA

784	328	UCAACUAAUCAAGUGAACAGC

785	329	UAUUACAAGGGACGUUCUCCA

786	330	UGAAGGGUAAUUGGAAUUGGU

787	331	UGAUUCACUCCAAAGGGUGUU

788	332	AUUAAUUCUUGGAGAGUACUA

789	333	AUUUGGAAUGAUUGCAGUCCA

790	334	UUAACAUGCUUAGAUACAAAG

791	335	AUAAGGAAUAUUUAUUAAGAA

792	336	UAAUUUGCAUCAUUAGAAUAA

793	337	AGCAGAACAAUAUUACUUGGU

794	338	CUUAAUUUGAUUUAGGUCUGU

795	339	AAUAGAAAUGUGAUUGAAGAU

796	340	UAUGAGCAAGUAAAUCUUUAU

797	341	UUUGAGAAUCUCCAUCAUAAU

798	342	AGUUCAAACAAUGACUUUGUA

799	343	UAGUUGGAGAGCUAAAUGUGC

800	344	AUAGGGUGCAUUCUGGUCUGC

801	345	UUGUAGUCUCCAAUAUGAAGG

802	346	AUAAGAAGCAAGACCAAGUCA

803	347	AUUAUGUAAUAUUAAAGGCAA

804	348	UUCUUGGAGAGUACUAUAAUU

805	349	UACACUUGUUAUCAAUGCACU

806	350	AAGAAGACAUGUUAACAUGCU

807	351	UUACAAGGGACGUUCUCCAGU

808	352	CAUCAUUAGAAUAAGAAGCAA

809	353	UUCAAUAAGGAAUAUUUAUUA

810	354	UACAUGAUAUAAGGUCCAGGU

811	355	AUUAGAACACAGACCACUAAG

812	356	AUUAUUACAAGGGACGUUCUC

813	357	UAGUGGUCAAUGCUGGAUGCC

814	358	AUCCAUAUUGUAGUCUCCAAU

815	359	AUAUGAGCAAGUAAAUCUUUA

816	360	UUUGCAUCUACAGUUGUAUAC

817	361	AGUAUGACCAGAGCGUCUGGA

818	362	UACAAGGGACGUUCUCCAGUA

819	363	UUACGAGGACAGUCAUUAGAA

820	364	AUUAAGAAGACAUGUUAACAU

821	365	UGAAGUCUGAAUGUAAAUUAU

822	366	ACACAGACCACUAAGAACAAU

823	367	CACUACAGAAUAGAGAACCCA

824	368	UUCAAACCAUAUUUAUUUGAA

825	369	UCAAAUGUUCUUCAUUAUCAC

826	370	UCAGGAAUAAAUCUGCUGUAA

827	371	UAUAAGGUCCAGGUUGAUUCA

828	372	ACAAACACUGGAGUACAUGCA

829	373	UUUAUAAAUAAUAUUUAAUCU

830	374	ACAGAGGUUAAACAAGAGCCA

831	375	UGUAGGACUGGAACCCACUGC

832	376	UGUCCAACCACCAUCAUAUUU

833	377	CAGUAGACUUUAAACAUUCGA

834	378	ACAUGCAACACAUUCCACAAA

835	379	UCAGAAGGACAUCCAUUUGAG

836	380	UCUAUCAUCUGCUUUCUUUUC

837	381	AUCAAUGCACUGUGAUUCUUG

838	382	UUGCAUCAUUAGAAUAAGAAG

839	383	UCAAAGUCUGCAAAUGCUGAC

840	384	AGUCCUAUUGAGUAUGGUCAU

841	385	UACCACAUAUUGACCACUUAC

842	386	AGUAACUCAAGUAUUAGCCCC

843	387	UAACAUGCUUAGAUACAAAGU

844	388	UCACAUACAUCAUCCCAUUUA

845	389	AUCAUUUAUAAAUAAUAUUUA

846	390	CUUGUGACAUAUUCAAACCAU

847	391	UGAUUGAAGAUUUGCAUUCCC

848	392	ACUUGUUAUCAAUGCACUGUG

849	393	AGGCAAGUCACAUAGCAUCAA

850	394	UUGAUUCACUCCAAAGGGUGU

851	395	AAUGUGAAGUUCACAAUACAA

852	396	AGGACAGUCAUUAGAACACAG

853	397	UGUUCUUUAGUAUGACCAGAG

854	398	UAUUGAGUAUGGUCAUAUUGU

855	399	GUAGUCUCCAAUAUGAAGGGU

856	400	AUGUAUUUCUAUAAUUAGAUG

857	401	UACUCUGUGCUAGGCACCAAG

858	402	UGUUAACAUGCUUAGAUACAA

859	403	AUAAAUGCAUGAGAAUGUGGA

860	404	AUUUCAAACUGGAAGGUACUA

861	405	UCCAAGAUUCCAUCUUCGUAA

862	406	UCCUUUACUUAGCACUACAAU

863	407	AAUACCAACGUAGAGAUGGUC

864	408	ACAUGAUAUAAGGUCCAGGUU

865	409	AUCUUUAUGUCAAUCACCAAA

866	410	UGAAAGAUACCUUUACUUUGG

867	411	AAGGCAAGUCUGUCUUACUGU

868	412	UGGAAUUGGUAUUUCAGUUGG

869	413	UAUAAAUAAUAUUUAAUCUCC

870	414	AUAAAUUCCCUCCUAAUAGUA

871	415	AUAAUUUGCAUCAUUAGAAUA

872	416	ACUUGUAGUGGUCAAUGCUGG

873	417	AUCUGCUUCAAAGUUAUUUUU

874	418	UAAGAAGACAUGUUAACAUGC

875	419	AAGCACUUCACAUACAUCAUC

876	420	UACAUCAUUUAUAAAUAAUAU

877	421	AUUGACCACUUACUCUGUGCU

878	422	UUCAAUGUCGUCAGGAAUAAA

879	423	AUACAUGAUAUAAGGUCCAGG

880	424	AAAUGUUCUUCAUUAUCACAU

881	425	AUUCAAACCAUAUUUAUUUGA

882	426	CAUUAGAACACAGACCACUAA

883	427	UGCUGGUUGCUUCCAGAUGUG

884	428	AUUGGAAUUGGUAUUUCAGUU

885	429	UAAUAUUAAAGGCAAGUCACA

886	430	CACUUCACAUACAUCAUCCCA

887	431	UAUCCUUUACUUAGCACUACA

888	432	AAUACUUUCCAAUAAUUACCA

889	433	UCCCUCCUAAUAGUAUCUGUG

890	434	AUGUGAUUGAAGAUUUGCAUU

891	435	AGAACAAUAUUACUUGGUGUA

892	436	AAUAUUUAUUAAGAAGACAUG

893	437	UCUAUCAAGUCUAUGUAUUUC

894	438	AAUAUUAAAGGCAAGUCACAU

895	439	UAUUUCAGUUGGUUGCUGUUC

896	440	GUAUGGAAUGACAAUUAGCUG

897	441	UCACAGCUUGCAUUAUUACAA

898	442	AAGUCUGUCUUACUGUGCUAC

899	443	AGUAUGGUCAUAUUGUUAGGA

900	444	UCAAUAAGGAAUAUUUAUUAA

901	445	AAACAAUGACUUUGUAAGUGG

902	446	UGGAUUCAUUUGUGAUACCAA

903	447	UAUUAAAGGCAAGUCACAUAG

904	448	UGGGAAUUUGGAAUGAUUGCA

905	449	AAUCUUGUAGGACUGGAACCC

906	450	AUCUCCAUCAAAGUCUGCAAA

907	451	UUAGAACACAGACCACUAAGA

908	452	UCACUAAGUAGAUGGUACUCU

909	453	UUUCUAUAAUUAGAUGUAUAA

910	454	UGCAUUGAAGUCUGAAUGUAA

911	455	UUUGCGCUCCGACCUAAACCA

912	456	UGAUUUAGGUCUGUCAGCUCC

913	457	AACCGGUGGGCUUCUUGUCGU

914	458	UGAAGAUUUGCAUUCCCAGAU

915	459	UUAUUUGAAUACUUUCCAAUA

916	460	UCCCAGUAGACUUUAAACAUU

917	461	UCAGUCAGAUCAAUAAAUGCA

918	462	CAUCCAUUUGAGAAUCUCCAU

919	463	UAGAAAUGUGAUUGAAGAUUU

920	464	ACAGCUCCUAAUUCACUCUUG

921	465	UUAGGUCUGUCAGCUCCCAGU

922	466	AAGACAUGUUAACAUGCUUAG

923	467	AUACCCAUUUGCAUCUACAGU

924	468	AAAUCUUUAUGUCAAUCACCA

925	469	CAGAGGUUAAACAAGAGCCAA

926	470	AUCAGGAAUUAGAUCACCAUU

927	471	UCCCAUUUAAUGUUUACAGUA

928	472	AGGCAAGUCUGUCUUACUGUG

929	473	UCUCAGUGAACUAUAAAGAAA

930	474	UAUUGACCACUUACUCUGUGC

931	475	AUGUAAAUUAUAGACUUCUCC

932	476	UCAGAUCAAUAAAUGCAUGAG

933	477	UGAGAAUGUGGAAUUCGCAUU

934	478	UUGCAUCUACAGUUGUAUACA

935	479	CUUAUUGCUGAAAUCUUGUAG

936	480	ACUUGGUGUAAGAUACAGUUU

937	481	AUAUUGUAGUCUCCAAUAUGA

938	482	ACAUCCAUUUGAGAAUCUCCA

939	483	UUAUCAAUGCACUGUGAUUCU

940	484	AUUACCAUGGGAUACAUCAUU

941	485	ACUUCACAUACAUCAUCCCAU

942	486	AUCAAAGUCUGCAAAUGCUGA

943	487	AUCCUUAAUUUGAUUUAGGUC

944	488	UGAAGCUGAAUGCCUAAUGAC

945	489	AGCAAGACCAAGUCAAGUGGA

946	490	AUUGCAGUCCACUCUUGUUUU

947	491	CAAACAAUGACUUUGUAAGUG

948	492	UCUAAUAAGAUCAUCUAAAAU

949	493	AUAACAGCUCCUAAUUCACUC

950	494	UAAGGAAUAUUUAUUAAGAAG

951	495	AAGGGUGUUAUCUUACGAGGA

952	496	UAAUGACAACUACCACAUAUU

953	497	UAUUACUUGGUGUAAGAUACA

954	498	AUCAUUAGAAUAAGAAGCAAG

955	499	CAAUAUAGUACUGACAGAGAA

956	500	AUUGUAGUCUCCAAUAUGAAG

957	501	UGACAACUACCACAUAUUGAC

958	502	ACUACAAUGUCCAAGAUUCCA

959	503	UCAGGAAUUAGAUCACCAUUG

960	504	ACCGGUGGGCUUCUUGUCGUU

961	505	AUGUCCAAGAUUCCAUCUUCG

962	506	AAUAAAUGCAUGAGAAUGUGG

963	507	AAGCAAGACCAAGUCAAGUGG

964	508	UCUUCGUAAAUGUCAAAGAAG

965	509	UUACCAUGGGAUACAUCAUUU

966	510	UUACAGAGGUUAAACAAGAGC

967	511	UUGCUGAAAUCUUGUAGGACU

968	512	UUGGAAUGAUUGCAGUCCACU

969	513	UAUGAAGGGUAAUUGGAAUUG

970	514	AUGAGCAAGUAAAUCUUUAUG

971	515	UUUGUAAGUGGUUGAAUUAGG

972	516	AACUACCACAUAUUGACCACU

973	517	UCAAACAAUGACUUUGUAAGU

974	518	AAUUCUUGGAGAGUACUAUAA

975	519	CUUACUGUGCUACCAAGUCAG

976	520	ACAAUUAGCUGGGAAUUUGGA

977	521	UGGAGUACAUGCAACACAUUC

978	522	AGAAAUGUGAUUGAAGAUUUG

979	523	UGCAUUCCCAGAUGCUGCCUA

980	524	UAAAUUCCCUCCUAAUAGUAU

981	525	AUUCUUUGUAUAUCCUUUACU

982	526	UUCCAAUAAUUACCAUGGGAU

983	527	UUCUUGAAAGAUACCUUUACU

984	528	UGAGCAAGUAAAUCUUUAUGU

985	529	CUGAAUGUAAAUUAUAGACUU

986	530	UGUGAGGGUAUGGAAUGACAA

987	531	AAUGUUCUUCAUUAUCACAUG

988	532	ACAGACACCGAUGAGAGCUAU

989	533	CCAACUUCGAGGGACAUUGUG

990	534	UAGUACUGACAGAGAAGUUUC

991	535	UUCACAGCUUGCAUUAUUACA

992	536	CAUAUUGACCACUUACUCUGU

993	537	AGGGACUACACUUGUUAUCAA

994	538	UUAUCACAUGAUAAGGAUAAG

995	539	AAUUACCAUGGGAUACAUCAU

996	540	ACUACACUUGUUAUCAAUGCA

997	541	UACAAUGUCCAAGAUUCCAUC

998	542	AUUUGCAUUGAAGUCUGAAUG

999	543	AUGAAGGGUAAUUGGAAUUGG

1000	544	ACUACAGAAUAGAGAACCCAA

1001	545	GAGAGCUAUAGCAGUAAGCAG

1002	546	AGAAUGUGGAAUUCGCAUUUU

1003	547	UCCAGGUUGAUUCACUCCAAA

1004	548	UUUCAAGAAAUCAAAUGUUCU

1005	549	ACCUAAACCAAGCACGUUGUA

1006	550	AAUAUAGUACUGACAGAGAAG

1007	551	GAUCUCACUAAGUAGAUGGUA

1008	552	UGUACAGCACUACAGAAUAGA

1009	553	UGUAAUAUUAAAGGCAAGUCA

1010	554	UUCCUUUCAAGAAAUCAAAUG

1011	555	AUCCAUUUGAGAAUCUCCAUC

1012	556	UAUCACAUGAUAAGGAUAAGU

1013	557	CAAUGCACUGUGAUUCUUGAA

1014	558	UGGAGAGCUAAAUGUGCGGAU

1015	559	UAAGAUUAUAAAUACACAAAC

1016	560	AUAAGAUUAUAAAUACACAAA

1017	561	UCUUGGAGAGUACUAUAAUUU

1018	562	AACAAUAUUACUUGGUGUAAG

1019	563	UCAAGAAAUCAAAUGUUCUUC

1020	564	UGUCGUCAGGAAUAAAUCUGC

1021	565	GAGUACAUGCAACACAUUCCA

1022	566	UAUGACCAGAGCGUCUGGAUA

1023	567	UCCAACCACCAUCAUAUUUUG

1024	568	CUGCAAAUGCUGACUGUCCAA

1025	569	UCCGACCUAAACCAAGCACGU

1026	570	UGUCAGCUCCCAGUAGACUUU

1027	571	AUUCUAUCAAGUCUAUGUAUU

1028	572	CUUAGCACUACAAUGUCCAAG

1029	573	UGAGAAUAGAAAUGUGAUUGA

1030	574	AAGCACGUUGUAUGGUAGUUG

1031	575	UAGGGUGCAUUCUGGUCUGCC

1032	576	UCAAUGCACUGUGAUUCUUGA

1033	577	UCCAAGUGUUUGAGAAUAGAA

1034	578	UCCAAUAUGAAGGGUAAUUGG

1035	579	CUUUCCAAUAAUUACCAUGGG

1036	580	UUAAUAUGAGCAAGUAAAUCU

1037	581	UUUCCUUUCAAGAAAUCAAAU

1038	582	UGACUUUGUAAGUGGUUGAAU

1039	583	GUAAGCAGAACAAUAUUACUU

1040	584	AUUCCAUCUUCGUAAAUGUCA

1041	585	UCUUACGAGGACAGUCAUUAG

1042	586	AAAUGUGAUUGAAGAUUUGCA

1043	587	ACAUAUUCAAACCAUAUUUAU

1044	588	UGUGACAUAUUCAAACCAUAU

1045	589	UUUGAAUACUUUCCAAUAAUU

1046	590	AAUGCCUAAUGACUCCGUGAU

1047	591	AUUUGAUUUAGGUCUGUCAGC

1048	592	AUAGGCAUCACAUGUCCAUUU

1049	593	UCAUGAUGCAAAUAAGAUUAU

1050	594	AGUUGGUUGCUGUUCAUCCAC

1051	595	AAGUCUAUGUAUUUCUAUAAU

1052	596	UGCACUGUGAUUCUUGAAAGA

1053	597	UGACAAUUAGCUGGGAAUUUG

1054	598	UGUCCAUUUGCAUACUAGAAA

1055	599	AUAGAAAUGUGAUUGAAGAUU

1056	600	UCCAACUUCGAGGGACAUUGU

1057	601	UUGAGAAUCUCCAUCAUAAUC

1058	602	GAUCACUAUAUUGUAUGCCAU

1059	603	UUCAUCCCAGAUCUCACUAAG

1060	604	UGAGUAUGGUCAUAUUGUUAG

1061	605	UGUGCUACCAAGUCAGAGUAC

1062	606	CAAACUGGAAGGUACUAGUGG

1063	607	ACACAAACACUGGAGUACAUG

1064	608	AUAUCAGGAAUUAGAUCACCA

1065	609	AAUGUUUACAGUAACUCAAGU

1066	610	UGUUUACAGUAACUCAAGUAU

1067	611	ACAUGCUUAGAUACAAAGUAA

1068	612	AUCACCAUUGAAAUCCAUAAU

1069	613	UAUUUCUUCAUGCCUGAAAAU

1070	614	UCAAGUCUAUGUAUUUCUAUA

1071	615	CAGAACAAUAUUACUUGGUGU

1072	616	UAGUUAAUAUGAGCAAGUAAA

1073	617	CUGAAAUCUUGUAGGACUGGA

1074	618	AAACAUUCGACGCGCCUCUUC

1075	619	UUCCUGCUCAUUUAAUUAUUU

1076	620	UGGGAAGAUAUGUCAGAAGGA

1077	621	UUUCAAUAAGGAAUAUUUAUU

1078	622	AUGACUCCGUGAUAUAUUCAC

1079	623	CAAACACUGGAGUACAUGCAA

1080	624	AAUGACUUUGUAAGUGGUUGA

1081	625	AAUGUCGUCAGGAAUAAAUCU

1082	626	UUCCAUUAUGUAAUAUUAAAG

1083	627	UUUGCAUUCCCAGAUGCUGCC

1084	628	UCAUAUUGUUAGGAUCUAAUG

1085	629	AAGUGUUUGAGAAUAGAAAUG

1086	630	AAGAUAACAGCUCCUAAUUCA

1087	631	AUUCUUGAAAGAUACCUUUAC

1088	632	AGUUUAAGGCAAGUCUGUCUU

1089	633	ACUACCACAUAUUGACCACUU

1090	634	AGGAGUUUAAGGCAAGUCUGU

1091	635	UUCAGUUGGUUGCUGUUCAUC

1092	636	AUUUAAUGUUUACAGUAACUC

1093	637	UCACAUGUCCAUUUGCAUACU

1094	638	UGCCCUUAUUGCUGAAAUCUU

1095	639	UGUAUAAGUCUAAUAAGAUCA

1096	640	UACAGAGGUUAAACAAGAGCC

1097	641	AAUUAGAUGUAUAAGUCUAAU

1098	642	GAGAAUAGAAAUGUGAUUGAA

1099	643	UGUCCAUCUCCAUCAAAGUCU

1100	644	UUCAAACAAUGACUUUGUAAG

1101	645	AAUGUAAAUUAUAGACUUCUC

1102	646	GUAUACAUGAUAUAAGGUCCA

1103	647	AGACUUCUCCAAGUGUUUGAG

1104	648	UACAGAAUAGAGAACCCAAAU

1105	649	CUUGUAGUGGUCAAUGCUGGA

1106	650	UUUGUAUAUCCUUUACUUAGC

1107	651	UUCUCCAAGUGUUUGAGAAUA

1108	652	UCAAACCAUAUUUAUUUGAAU

1109	653	AAUGACUCCGUGAUAUAUUCA

1110	654	AUUCUUGGAGAGUACUAUAAU

1111	655	CAUCAAAGUCUGCAAAUGCUG

1112	656	AGACAUGUUAACAUGCUUAGA

1113	657	UGUGAUUGAAGAUUUGCAUUC

1114	658	AAGAUACCUUUACUUUGGGUU

1115	659	AGAAUAUUUCUUCAUGCCUGA

1116	660	AUUUGCAUCUACAGUUGUAUA

1117	661	UCCAUUUGAGAAUCUCCAUCA

1118	662	UCCAAAGAAUAUUUCUUCAUG

1119	663	AAUAAUUACCAUGGGAUACAU

1120	664	UGGAAAUGUGAAGUUCACAAU

1121	665	ACACCGAUGAGAGCUAUAGCA

1122	666	ACUGGAGUACAUGCAACACAU

1123	667	AGGUCUGUCAGCUCCCAGUAG

1124	668	UUAGGAGUUUAAGGCAAGUCU

1125	669	AUAUAGUACUGACAGAGAAGU

1126	670	CCAUUUGAGAAUCUCCAUCAU

1127	671	UGUCUUACUGUGCUACCAAGU

1128	672	ACAGCUUGCAUUAUUACAAGG

1129	673	AGUAGACUUUAAACAUUCGAC

1130	674	UACAGUAACUCAAGUAUUAGC

1131	675	UGAGAGCUAUAGCAGUAAGCA

1132	676	ACCAUUGAAAUCCAUAAUUAG

1133	677	AGCUUGCAUUAUUACAAGGGA

1134	678	CAUAUUUCAAACUGGAAGGUA

1135	679	AACCAAGCACGUUGUAUGGUA

1136	680	UCUGAAUGUAAAUUAUAGACU

1137	681	ACCAUAUUUAUUUGAAUACUU

1138	682	CUUGUUAUCAAUGCACUGUGA

1139	683	AAAUCAAAUGUUCUUCAUUAU

1140	684	UAUGGUCAUAUUGUUAGGAUC

1141	685	AUCUUCAGUCAGAUCAAUAAA

1142	686	UAUGGUAGUUGGAGAGCUAAA

1143	687	UCCUUAAUUUGAUUUAGGUCU

1144	688	AUCCCAGAUCUCACUAAGUAG

1145	689	AAUAAGAAGCAAGACCAAGUC

1146	690	AAACCGGUGGGCUUCUUGUCG

1147	691	AGAUCUCACUAAGUAGAUGGU

1148	692	AUUUCUAUAAUUAGAUGUAUA

1149	693	UGGAAUGAUUGCAGUCCACUC

1150	694	UUCAGUCAGAUCAAUAAAUGC

1151	695	CACAUGUCCAUUUGCAUACUA

1152	696	GUCAGGAAUAAAUCUGCUGUA

1153	697	ACCCAUUUGCAUCUACAGUUG

1154	698	AGGAUCUAAUGUUUGAUUUUG

1155	699	AUAUUCAAACCAUAUUUAUUU

1156	700	AGGUUGAUUCACUCCAAAGGG

1157	701	GAAUGAUUGCAGUCCACUCUU

1158	702	UCGACGCGCCUCUUCACAGCU

1159	703	AUGACAAUUAGCUGGGAAUUU

1160	704	AGAAUAAGAAGCAAGACCAAG

1161	705	AGCUAAGCACUUCACAUACAU

1162	706	UCCAUUUGCAUACUAGAAAAU

1163	707	CACAUAUUGACCACUUACUCU

1164	708	AUAUUUAUUUGAAUACUUUCC

1165	709	AAUUGGUAUUUCAGUUGGUUG

1166	710	AGCACUACAAUGUCCAAGAUU

1167	711	AUGCCUAAUGACUCCGUGAUA

1168	712	UCAUCAUGAUGCAAAUAAGAU

1169	713	ACCUGCUGUGAUGAAGCUGAA

1170	714	AAACACUGGAGUACAUGCAAC

1171	715	UGCAUGAGAAUGUGGAAUUCG

1172	716	GUCCAAGAUUCCAUCUUCGUA

1173	717	CUACCACAUAUUGACCACUUA

1174	718	UCCAUCAUCAUGAUGCAAAUA

1175	719	CAAUGUCCAAGAUUCCAUCUU

1176	720	UUAUUAAGAAGACAUGUUAAC

1177	721	AGAAGGACAUCCAUUUGAGAA

1178	722	UCAGAGUACCCGAUCACUAUA

1179	723	AAUACACAAACACUGGAGUAC

1180	724	CUGAAUGCCUAAUGACUCCGU

1181	725	AUGUGAAGUUCACAAUACAAA

1182	726	AGCAAGUAAAUCUUUAUGUCA

1183	727	AAUUGGAAUUGGUAUUUCAGU

1184	728	AAUAUUACUUGGUGUAAGAUA

1185	729	CUUGGUGUAAGAUACAGUUUG

1186	730	GUGAUUCUUGAAAGAUACCUU

1187	731	UCACCAUUGAAAUCCAUAAUU

1188	732	UGUAGUGGUCAAUGCUGGAUG

1189	733	UCUUCAUUAUCACAUGAUAAG

1190	734	AAGUUCAAACAAUGACUUUGU

1191	735	UAUUUCAAACUGGAAGGUACU

1192	736	AAGUCUGAAUGUAAAUUAUAG

1193	737	AAUGUCCAAGAUUCCAUCUUC

1194	738	UGUUAUCUUACGAGGACAGUC

1195	739	GUGUUUGAGAAUAGAAAUGUG

1196	740	AGACCUUGUGACAUAUUCAAA

1197	741	AGAGCUAUAGCAGUAAGCAGA

1198	742	AAGGGUAAUUGGAAUUGGUAU

1199	743	UCCUGCUCAUUUAAUUAUUUU

1200	744	CUGGAGUACAUGCAACACAUU

1201	745	ACACAGACACCGAUGAGAGCU

1202	746	AUCAUGAUGCAAAUAAGAUUA

1203	747	AUUUGAAUACUUUCCAAUAAU

1204	748	AGAUUAUAAAUACACAAACAC

1205	749	GUAGUUGGAGAGCUAAAUGUG

1206	750	AGUCAGAUCAAUAAAUGCAUG

1207	751	UUUCAACUAAUCAAGUGAACA

1208	752	ACUUCGAGGGACAUUGUGAGG

1209	753	UUAUUACAAGGGACGUUCUCC

1210	754	UGGUUGCUGUUCAUCCACAAA

1211	755	ACAUGUCCAUUUGCAUACUAG

1212	756	ACAGUUGUAUACAUGAUAUAA

1213	757	UGCUGCCUACAGCAGUUUCCU

1214	758	AUUAGAUGUAUAAGUCUAAUA

1215	759	UUCGACGCGCCUCUUCACAGC

1216	760	AAAUGCAUGAGAAUGUGGAAU

1217	761	UCUAUAAUUAGAUGUAUAAGU

1218	762	GACAGAGAAGUUUCCAUCCAA

1219	763	UACAGCAGUUUCCUUUCAAGA

1220	764	CUAUUGAGUAUGGUCAUAUUG

1221	765	GUAUAAGUCUAAUAAGAUCAU

1222	766	CAGUCAUUAGAACACAGACCA

1223	767	AUUCAAUGUCGUCAGGAAUAA

1224	768	AUGAUAUAAGGUCCAGGUUGA

1225	769	AUUAUCACAUGAUAAGGAUAA

1226	770	GUGUUCUUUAGUAUGACCAGA

1227	771	CAGAGUGUGCCCUUAUUGCUG

1228	772	AAGCUAAGCACUUCACAUACA

1229	773	CUUUAGUAUGACCAGAGCGUC

1230	774	UACGAGGACAGUCAUUAGAAC

1231	775	AUGUAUAAGUCUAAUAAGAUC

1232	776	CAUAUUGUUAGGAUCUAAUGU

1233	777	AUGUCAGAAGGACAUCCAUUU

1234	778	UGUGCUAGGCACCAAGCUAAG

1235	779	AUUUGCAUCAUUAGAAUAAGA

1236	780	CAAAGGGUGUUAUCUUACGAG

1237	781	AGCAGUAAGCAGAACAAUAUU

1238	782	AGAACAAUAACUUUAACAAAA

1239	783	CAUUUGAGAAUCUCCAUCAUA

1240	784	AUGCACUGUGAUUCUUGAAAG

1241	785	ACACUGGAGUACAUGCAACAC

1242	786	CCUUAUUGCUGAAAUCUUGUA

1243	787	AUGACCAGAGCGUCUGGAUAG

1244	788	AGGCCUGCUGGUUGCUUCCAG

1245	789	AGGUUUACAGAGGUUAAACAA

1246	790	AAAUUAUAGACUUCUCCAAGU

1247	791	AGAUGCUGCCUACAGCAGUUU

1248	792	UGGUUGGAUUCAUUUGUGAUA

1249	793	CAUGAGAAUGUGGAAUUCGCA

1250	794	GUACUGACAGAGAAGUUUCCA

1251	795	GUCCAGGUUGAUUCACUCCAA

1252	796	CCGACCUAAACCAAGCACGUU

1253	797	AGUUGGAGAGCUAAAUGUGCG

1254	798	CAUAUUGUAGUCUCCAAUAUG

1255	799	CAUUAUGUAAUAUUAAAGGCA

1256	800	CUACACUUGUUAUCAAUGCAC

1257	801	AACCAUAUUUAUUUGAAUACU

1258	802	AUAUUAAAGGCAAGUCACAUA

1259	803	ACCAAGCUAAGCACUUCACAU

1260	804	GAAAGAUACCUUUACUUUGGG

1261	805	UUAAGGCAAGUCUGUCUUACU

1262	806	AAUUUGCAUCAUUAGAAUAAG

1263	807	CAUGAUAUAAGGUCCAGGUUG

1264	808	AUAGCAGUAAGCAGAACAAUA

1265	809	CAAUAAAUGCAUGAGAAUGUG

1266	810	AGAAGUUUCCAUCCAAAUUUU

1267	811	AAGCAUCUGCUUCAAAGUUAU

1268	812	CACUUGUUAUCAAUGCACUGU

1269	813	AUUCGACGCGCCUCUUCACAG

1270	814	AAGCUGAAUGCCUAAUGACUC

1271	815	UCCAUAUUGUAGUCUCCAAUA

1272	816	AUAUUAAUAAUGACAACUACC

1273	817	CUUUAAACAUUCGACGCGCCU

1274	818	CUUCGAGGGACAUUGUGAGGG

1275	819	AUGAAGCUGAAUGCCUAAUGA

1276	820	GAACCCACUGCUUCAUCCCAG

1277	821	AAAUGUGAAGUUCACAAUACA

1278	822	ACCGAUGAGAGCUAUAGCAGU

1279	823	CUUUGUAUAUCCUUUACUUAG

1280	824	GUCGUCAGGAAUAAAUCUGCU

1281	825	AGUCUGCAAAUGCUGACUGUC

1282	826	UGUUAUCAAUGCACUGUGAUU

1283	827	AUACACAAACACUGGAGUACA

1284	828	GUUGGAGAGCUAAAUGUGCGG

1285	829	AUUGAAGUCUGAAUGUAAAUU

1286	830	CCUUGUGACAUAUUCAAACCA

1287	831	UCAGCUCCCAGUAGACUUUAA

1288	832	ACAGCACUACAGAAUAGAGAA

1289	833	CUACAAUGUCCAAGAUUCCAU

1290	834	ACUGCUUCAUCCCAGAUCUCA

1291	835	ACCACUUACUCUGUGCUAGGC

1292	836	AGAAUAGAGAACCCAAAUUUU

1293	837	ACUAAGAACAAUAACUUUAAC

1294	838	AUUGUGAGGGUAUGGAAUGAC

1295	839	ACAUCAUUUAUAAAUAAUAUU

1296	840	UUCAAACUGGAAGGUACUAGU

1297	841	ACUCCAAAGGGUGUUAUCUUA

1298	842	UGAGGGUAUGGAAUGACAAUU

1299	843	ACAAUGUCCAAGAUUCCAUCU

1300	844	CUAAGUAGAUGGUACUCUUUU

1301	845	CCAUUUGCAUCUACAGUUGUA

1302	846	AAGAAGCAAGACCAAGUCAAG

1303	847	AGUGGUUGAAUUAGGAGUUUA

1304	848	UAUGUAAUAUUAAAGGCAAGU

1305	849	AAGAUUAUAAAUACACAAACA

1306	850	AAUCUCAGUGAACUAUAAAGA

1307	851	CAACUACCACAUAUUGACCAC

1308	852	ACAAGGGACGUUCUCCAGUAA

1309	853	UGACUCCGUGAUAUAUUCACA

1310	854	CUACCAAGUCAGAGUACCCGA

1311	855	AUGAAACCGGUGGGCUUCUUG

1312	856	UGUGAAGUUCACAAUACAAAA

1313	857	ACUGGAAGGUACUAGUGGUGG

1314	858	UAUUAAGAAGACAUGUUAACA

1315	859	UCUUCACAGCUUGCAUUAUUA

1316	860	ACAUGUUAACAUGCUUAGAUA

1317	861	AAGAUAUGUCAGAAGGACAUC

1318	862	GUUUAAGGCAAGUCUGUCUUA

1319	863	AUUCCUGCUCAUUUAAUUAUU

1320	864	GAAGACAUGUUAACAUGCUUA

1321	865	AAUAUGAAGGGUAAUUGGAAU

1322	866	CAAAUGCUGACUGUCCAACCA

1323	867	UAUAUACAAAGUGCUUUAAAA

1324	868	UAAUGACUCCGUGAUAUAUUC

1325	869	GUCAUUAGAACACAGACCACU

1326	870	AUCCCAUUUAAUGUUUACAGU

1327	871	ACAUCAUCCCAUUUAAUGUUU

1328	872	AUACCUUUACUUUGGGUUUAA

1329	873	GAAUAUUUCUUCAUGCCUGAA

1330	874	GUCUGUCUUACUGUGCUACCA

1331	875	AGUGUUUGAGAAUAGAAAUGU

1332	876	AUCAUCAUGAUGCAAAUAAGA

1333	877	GUAACUCAAGUAUUAGCCCCA

1334	878	GUUGUAUACAUGAUAUAAGGU

1335	879	UCUCACUAAGUAGAUGGUACU

1336	880	UGAUGAAGCUGAAUGCCUAAU

1337	881	UGCGCUCCGACCUAAACCAAG

1338	882	CAGCUUGCAUUAUUACAAGGG

1339	883	UGGAACCCACUGCUUCAUCCC

1340	884	AUAAGUCUAAUAAGAUCAUCU

1341	885	AAAGGGUGUUAUCUUACGAGG

1342	886	AACGUAGAGAUGGUCAAGAAA

1343	887	AGGGUAUGGAAUGACAAUUAG

1344	888	AUUAGCUGGGAAUUUGGAAUG

1345	889	ACUUCUCCAAGUGUUUGAGAA

1346	890	UCAGUGAACUAUAAAGAAAAA

1347	891	UCUUCAGUCAGAUCAAUAAAU

1348	892	UGGUUGAAUUAGGAGUUUAAG

1349	893	AUGGGAUACAUCAUUUAUAAA

1350	894	CCUUAAUUUGAUUUAGGUCUG

1351	895	AUCAAUAAAUGCAUGAGAAUG

1352	896	AUUUGAGAAUCUCCAUCAUAA

1353	897	UUAGCACUACAAUGUCCAAGA

1354	898	AGAGUGUGCCCUUAUUGCUGA

1355	899	UCCCAUAUUUCAAACUGGAAG

1356	900	GACUUUAAACAUUCGACGCGC

1357	901	GAUUGCAGUCCACUCUUGUUU

1358	902	GUCCAUCUCCAUCAAAGUCUG

1359	903	ACUUUAAACAUUCGACGCGCC

1360	904	CUGUGCUACCAAGUCAGAGUA

1361	905	UCCUAUUGAGUAUGGUCAUAU

1362	906	AGUAUAAUUUGCAUCAUUAGA

1363	907	ACCAACGUAGAGAUGGUCAAG

1364	908	ACAUUCGACGCGCCUCUUCAC

1365	909	CAGUUGGUUGCUGUUCAUCCA

1366	910	CUGUCUUACUGUGCUACCAAG

1367	911	AUGCAACACAUUCCACAAAGG

1368	912	AGGACUGGAACCCACUGCUUC

1369	913	UCUCCAAGUGUUUGAGAAUAG

1370	914	UGCUUCAUCCCAGAUCUCACU

1371	915	AAUAUUUCUUCAUGCCUGAAA

1372	916	AGAAAUCAAAUGUUCUUCAUU

1373	917	UCUCCAUCAAAGUCUGCAAAU

1374	918	UCAAUAAAUGCAUGAGAAUGU

1375	919	AUCACAUGAUAAGGAUAAGUU

1376	920	ACAGUCAUUAGAACACAGACC

1377	921	UCUGUCAGCUCCCAGUAGACU

1378	922	CAUUGAAAUCCAUAAUUAGUG

1379	923	CUUUGUAAGUGGUUGAAUUAG

1380	924	AAGGCAAGUCACAUAGCAUCA

1381	925	ACUUUGUAAGUGGUUGAAUUA

1382	926	AAAUAAGAUUAUAAAUACACA

1383	927	AUACAUCAUCCCAUUUAAUGU

1384	928	UAAGGUCCAGGUUGAUUCACU

1385	929	GACCACUAAGAACAAUAACUU

1386	930	CUGUGAUGAAGCUGAAUGCCU

1387	931	UGCUAGGCACCAAGCUAAGCA

1388	932	GUACCCGAUCACUAUAUUGUA

1389	933	CACCGAUGAGAGCUAUAGCAG

1390	934	UCCCAGAUGCUGCCUACAGCA

1391	935	CAGUCAGAUCAAUAAAUGCAU

1392	936	AUGCAUGAGAAUGUGGAAUUC

1393	937	UGUAUACAUGAUAUAAGGUCC

1394	938	UCCAAUAAUUACCAUGGGAUA

1395	939	CAAUAUUACUUGGUGUAAGAU

1396	940	AAAGGCAAGUCACAUAGCAUC

1397	941	AUUGGUAUUUCAGUUGGUUGC

1398	942	UCCUUUCAAGAAAUCAAAUGU

1399	943	GUAUUUCUAUAAUUAGAUGUA

1400	944	UCCAUUAUGUAAUAUUAAAGG

1401	945	AACACUGGAGUACAUGCAACA

1402	946	AAGAUUUGCAUUCCCAGAUGC

1403	947	GUAGACUUUAAACAUUCGACG

1404	948	CCACUAAGAACAAUAACUUUA

1405	949	GAUUCUUGAAAGAUACCUUUA

1406	950	CAAUUAGCUGGGAAUUUGGAA

1407	951	AGUCUAUGUAUUUCUAUAAUU

1408	952	CACGUUGUAUGGUAGUUGGAG

1409	953	UGCCUAAUGACUCCGUGAUAU

1410	954	UGAAACCGGUGGGCUUCUUGU

1411	955	GUUGAUUCACUCCAAAGGGUG

1412	956	AAUUAGAUCACCAUUGAAAUC

1413	957	UGAUAAAUUCCCUCCUAAUAG

1414	958	AUUCACUCCAAAGGGUGUUAU

1415	959	UGAAUACUUUCCAAUAAUUAC

1416	960	AAUGCUGACUGUCCAACCACC

1417	961	AAUGCACUGUGAUUCUUGAAA

1418	962	GAAUUGGUAUUUCAGUUGGUU

1419	963	AUAAUUACCAUGGGAUACAUC

1420	964	AGAUCAAUAAAUGCAUGAGAA

1421	965	GCUGAAAUCUUGUAGGACUGG

1422	966	AUUCAUUUGUGAUACCAAAAA

1423	967	GUUCAAACAAUGACUUUGUAA

1424	968	AUUCCAUUAUGUAAUAUUAAA

1425	969	GUACAUGCAACACAUUCCACA

1426	970	AUUCCCAGAUGCUGCCUACAG

1427	971	AGUCUGAAUGUAAAUUAUAGA

1428	972	CACAGCUUGCAUUAUUACAAG

1429	973	CAAUAUGAAGGGUAAUUGGAA

1430	974	CAUCUCCAUCAAAGUCUGCAA

1431	975	AGUCUAAUAAGAUCAUCUAAA

1432	976	UGCUGUGAUGAAGCUGAAUGC

1433	977	CUUUACUUAGCACUACAAUGU

1434	978	AUGUUAACAUGCUUAGAUACA

1435	979	UGCUUAGAUACAAAGUAAAAA

1436	980	AUGGUCAUAUUGUUAGGAUCU

1437	981	AACAUUCGACGCGCCUCUUCA

1438	982	UACCUUUACUUUGGGUUUAAA

1439	983	GUGAUGAAGCUGAAUGCCUAA

1440	984	AGGGCACAUUAAUUCUUGGAG

1441	985	ACAGCAGUUUCCUUUCAAGAA

1442	986	AUGCUUAGAUACAAAGUAAAA

1443	987	ACUCCGUGAUAUAUUCACAAA

1444	988	UCUUUAUGUCAAUCACCAAAA

1445	989	GAUUGAAGAUUUGCAUUCCCA

1446	990	AUUAGGAGUUUAAGGCAAGUC

1447	991	AAUUUGGAAUGAUUGCAGUCC

1448	992	UCCCAGAUCUCACUAAGUAGA

1449	993	CACUAAGUAGAUGGUACUCUU

1450	994	UGCAUCAUUAGAAUAAGAAGC

1451	995	AGAUGUAUAAGUCUAAUAAGA

1452	996	UUGUGAGGGUAUGGAAUGACA

1453	997	AGUCAGAGUACCCGAUCACUA

1454	998	CUGUGCUAGGCACCAAGCUAA

1455	999	GUAUAAUUUGCAUCAUUAGAA

1456	1000	UAAUUACCAUGGGAUACAUCA

1457	1001	CACAUUAAUUCUUGGAGAGUA

1458	1002	CUUGAAAGAUACCUUUACUUU

1459	1003	CUGCCUACAGCAGUUUCCUUU

1460	1004	AAGACCAAGUCAAGUGGACAC

1461	1005	GGAAUUGGUAUUUCAGUUGGU

1462	1006	CCAUAUUUCAAACUGGAAGGU

1463	1007	GAACAAUAUUACUUGGUGUAA

1464	1008	CAAGUCUAUGUAUUUCUAUAA

1465	1009	AAGAUUCCAUCUUCGUAAAUG

1466	1010	ACAUGAUAAGGAUAAGUUUUU

1467	1011	ACAUACAUCAUCCCAUUUAAU

1468	1012	GACAUGUUAACAUGCUUAGAU

1469	1013	UGGUAGUUGGAGAGCUAAAUG

1470	1014	CUAUAGCAGUAAGCAGAACAA

1471	1015	CUUCAUCCCAGAUCUCACUAA

1472	1016	CUCUGUGCUAGGCACCAAGCU

1473	1017	AAGGUCCAGGUUGAUUCACUC

1474	1018	GACUGGAACCCACUGCUUCAU

1475	1019	AUCACAUGUCCAUUUGCAUAC

1476	1020	CUACAGAAUAGAGAACCCAAA

1477	1021	AAUGACAAUUAGCUGGGAAUU

1478	1022	GUAAAUCUUUAUGUCAAUCAC

1479	1023	GUAUGGUAGUUGGAGAGCUAA

1480	1024	CAUCCUUAAUUUGAUUUAGGU

1481	1025	AUCUUACGAGGACAGUCAUUA

1482	1026	CACAUGAUAAGGAUAAGUUUU

TABLE 5

Results for ABCC4. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_	siRNA guide strand/
NO	id	AS Sequence

1483	1	UUAACAGUGAUGACUUCCCUG

1484	2	UUGACAAAUACACAGUUCGAA

1485	3	UUAAGAUCUAGCUUCUCGGUU

1486	4	UAACACUUUAUGAUUGCUCUU

1487	5	UUCACUUUCCUCAUUAUCCUU

1488	6	UUCAAUAUCAGAAUCUGACUU

1489	7	UUAAACCUGAAUAAAUUCCUA

1490	8	UAGAAUACCAAUAGAGAUCUU

1491	9	UGCACUGAGAGGAUCGUCCAG

1492	10	UCAUCUUCCUCUAAUCUCCGU

1493	11	UAUAACUUCAUUCAUGGUCCU

1494	12	UUUGACAAAUACACAGUUCGA

1495	13	AUAACUUCAUUCAUGGUCCUG

1496	14	UUAAAGAAGGCUUCUGUGCGU

1497	15	UGUAAGAACACUGUCACCUGA

1498	16	UAAGAUUUCCAGUAACACUUU

1499	17	UCAUUCAUGGUCCUGAUCCUG

1500	18	UCAGAAUCUGACUUGCAGCUU

1501	19	UACACGGGCAGCAUCUUGCCG

1502	20	AUACAUAUCAUCUUCCUCUAA

1503	21	UGAAGAGUUAACAAGGACGUA

1504	22	UUUGUGAAGAGUUAACAAGGA

1505	23	UCUAUCAAAGAAUAAUACCGG

1506	24	UGAUAUCUCAUCAAGUAGCAA

1507	25	UGACAUUUAGCAUACUUUGUU

1508	26	AAACUUGUUCACAUCAUUGGA

1509	27	UUUACAGUGACAUUUAGCAUA

1510	28	AUUUACAGUGACAUUUAGCAU

1511	29	AAGCACAUAGGCAACAUCUUG

1512	30	UUCUCGGUUACAUUUCCUCCU

1513	31	UAAACCUGAAUAAAUUCCUAA

1514	32	AAUCUUGGAAAUCUCCUUCUU

1515	33	UAUUACUCCUCAGAGUUCCCG

1516	34	UUCCUAUUGGAUUUCUAUCAA

1517	35	AUACCAAUAGAGAUCUUGCUA

1518	36	UUUCCAGUAACACUUUAUGAU

1519	37	UUGCUCUUGUUAAAGAAGGCU

1520	38	UAUCAAAGAAUAAUACCGGAG

1521	39	UGAGGUACUGCAACUGAUGAG

1522	40	UUCCGCAUCUACUGCACUGAG

1523	41	UGAAUACAUAUCAUCUUCCUC

1524	42	AUCACCAUCCUCCAACAGCUG

1525	43	UUGCAACUCCUCUCCAAGGUG

1526	44	UUGUUAAAGAAGGCUUCUGUG

1527	45	UCUUGAUACACUGCUCUUGCA

1528	46	UUUCAGAAUUGACUCAAACAU

1529	47	AGUGAUGAGAACAACUUCCCA

1530	48	UCAAUAUCAGAAUCUGACUUG

1531	49	AAUCUUGAAGCACAUAGGCAA

1532	50	UCUUCCAUGCACGCUGACCAG

1533	51	AAGAUUUCCAGUAACACUUUA

1534	52	UACUGCACUGAGAGGAUCGUC

1535	53	UAAGAUCUAGCUUCUCGGUUA

1536	54	UUAGUGUGGGAGUUCCUGGAA

1537	55	AACACUUUAUGAUUGCUCUUG

1538	56	UACACUGCUCUUGCAAGGUUU

1539	57	AUAUCAGAAUCUGACUUGCAG

1540	58	AUAGAGAUCUUGCUAUGCCAA

1541	59	AAUACAUAUCAUCUUCCUCUA

1542	60	UACACAGUUCGAACAAGUGUC

1543	61	UAUUGGAUUUCUAUCAAAGAA

1544	62	AUCAUCUUCCUCUAAUCUCCG

1545	63	UAGAAGAUUGUUGAGACCAAA

1546	64	UACCAAUAGAGAUCUUGCUAU

1547	65	UUGUGAAGAGUUAACAAGGAC

1548	66	UGCUCUUGCAAGGUUUACCCG

1549	67	AUACUUUGUUUGUUUGCCCAG

1550	68	UUAUACCAGUUAUAACUUCAU

1551	69	UAAAUUCCUAAGUACCAGUUA

1552	70	UUGCCUCUGACACCCUCUCAA

1553	71	UAACUUCCGCAUCUACUGCAC

1554	72	UAUUCCUAUCUCCAUCCAGAG

1555	73	AUACACAGUUCGAACAAGUGU

1556	74	UUACUCCUCAGAGUUCCCGAG

1557	75	AACAAGGACGUAGAAUACCAA

1558	76	UUUAGCAUACUUUGUUUGUUU

1559	77	UCAGCAUCUUGAUACACUGCU

1560	78	UGCAGCUUUGAGGUACUGCAA

1561	79	AGAUUGUUGAGACCAAACCGA

1562	80	UUGAGGUACUGCAACUGAUGA

1563	81	UAUACCAGUUAUAACUUCAUU

1564	82	UUAGCAUACUUUGUUUGUUUG

1565	83	UUCUUUAUCCCAGAACCCUUG

1566	84	AAUACCAAUAGAGAUCUUGCU

1567	85	UUCAGAAUUGACUCAAACAUU

1568	86	UCUGAGGCAGGAACUUCUCAG

1569	87	UGUCACCUGAUCAAACUUGUU

1570	88	UCUUUCAAUAUCAGAAUCUGA

1571	89	UUGGAAAUCUCCUUCUUUCUC

1572	90	UUACAUUUCCUCCUCCAUUUA

1573	91	AUCUUGGAAAUCUCCUUCUUU

1574	92	UUCUAUCAAAGAAUAAUACCG

1575	93	UGCGCUGUGAUAUCUCAUCAA

1576	94	AAGAUUGUUGAGACCAAACCG

1577	95	UUGCAAGGUUUACCCGUGCUU

1578	96	UCCAUUUACAGUGACAUUUAG

1579	97	UGAGACACAUAGGCAAUUCUU

1580	98	UAAGUACCAGUUAAGAUCUAG

1581	99	AUUUAGCAUACUUUGUUUGUU

1582	100	UCUUGUUAAAGAAGGCUUCUG

1583	101	AAUAGAGAUCUUGCUAUGCCA

1584	102	UGUCAGCAUCUUGAUACACUG

1585	103	UACAGUGACAUUUAGCAUACU

1586	104	UGAGCAGAGGUUCGCGUCCUG

1587	105	UGACAGUAAAGGAAAGGCCUU

1588	106	ACAAGUGUCUGCUAACUUCCG

1589	107	AUACACUGCUCUUGCAAGGUU

1590	108	UCACAGUCAGAUCACCAUCCU

1591	109	UUUGAGGUACUGCAACUGAUG

1592	110	ACACAUAGGCAAUUCUUCCAU

1593	111	AUAGAUGUCAGCAUCUUGAUA

1594	112	UUUACCCGUGCUUUCUGCCCU

1595	113	UUCCUGGAACUGGAGGUUGUU

1596	114	AGUCAGAUCACCAUCCUCCAA

1597	115	UUUAUCCCAGAACCCUUGCAA

1598	116	UUCCUAUCUCCAUCCAGAGUA

1599	117	UUCCUCAUUAUCCUUCUUUAA

1600	118	AAUCUGACUUGCAGCUUUGAG

1601	119	CACAGUUCGAACAAGUGUCUG

1602	120	UACCAGUUAAGAUCUAGCUUC

1603	121	AGUUCGAACAAGUGUCUGCUA

1604	122	AAGUGUCUGCUAACUUCCGCA

1605	123	UCUGACUUGCAGCUUUGAGGU

1606	124	UCUCGGUUACAUUUCCUCCUC

1607	125	UUCAUUCAUGGUCCUGAUCCU

1608	126	UACGAUUCCUUAGUGUGGGAG

1609	127	UCCAACAGCUGUAAAUCCUUU

1610	128	UUGUGCAAAGUUUGUGAAGAG

1611	129	AAUAUCAGAAUCUGACUUGCA

1612	130	UCUUCCUCUAAUCUCCGUUUA

1613	131	AUAAGAUUUCCAGUAACACUU

1614	132	AUCCUGCACAUGCACCAUCUU

1615	133	AUCUUUCAAUAUCAGAAUCUG

1616	134	UCCUGCACAUGCACCAUCUUU

1617	135	AACCCUUGCAACUCCUCUCCA

1618	136	UCCUUCUUUCUCAAAUUGGUA

1619	137	UACUAAGACGAAGUGCCUCAA

1620	138	UCACCAUCCUCCAACAGCUGU

1621	139	UGUCUUUGGAGAAACGAUUUA

1622	140	UGUGAUCACACUGCCGAGGAG

1623	141	ACCACAGCUAACAAUUCGCCA

1624	142	UUCACAUCAUUGGACAGCAGA

1625	143	UUCUGCCCUCCACUCAGCGUG

1626	144	UUUAUGAUUGCUCUUGUUAAA

1627	145	ACCAGUUAUAACUUCAUUCAU

1628	146	UCUCCAUCCAGAGUAGGGCAG

1629	147	CAUCUUGAUACACUGCUCUUG

1630	148	UUCAAGGAGGGUCUAGAAGAU

1631	149	UAAAGAAGGCUUCUGUGCGUC

1632	150	UUGAUACACUGCUCUUGCAAG

1633	151	UUUCCUCCUCCAUUUACAGUG

1634	152	AAGUGUCCAAUGUCUUUGGAG

1635	153	UCUGAGAAGGUACGAUUCCUU

1636	154	ACAAAUACACAGUUCGAACAA

1637	155	UCAGAAUCUUGGAAAUCUCCU

1638	156	UUUCUGCCCUCCACUCAGCGU

1639	157	AGUGUCUGCUAACUUCCGCAU

1640	158	UAAAGGAAAGGCCUUGUAGAG

1641	159	UUCUGUGCGUCAUUCUCAGCU

1642	160	UCCUUAGUGUGGGAGUUCCUG

1643	161	CUGACUUGCAGCUUUGAGGUA

1644	162	AACAGUGAUGACUUCCCUGCU

1645	163	UCUAGCUUCUCGGUUACAUUU

1646	164	UCUAGAAGAUUGUUGAGACCA

1647	165	UAACCGUCAGCCGCACAGCCC

1648	166	UUGGACAGCAGAUUGACUAUC

1649	167	UAGGAACUCAGUGUAAGUCCC

1650	168	AUGCACGCUGACCAGCCCGUG

1651	169	AUAUCAUCUUCCUCUAAUCUC

1652	170	UUCCAGUAACACUUUAUGAUU

1653	171	ACUGAGAGGAUCGUCCAGGAG

1654	172	UUACCCGUGCUUUCUGCCCUC

1655	173	UAUCAUCUUCCUCUAAUCUCC

1656	174	CUUAACAGUGAUGACUUCCCU

1657	175	AAAUUCAUCCCUCUGAGGCAG

1658	176	UCCAAGUGUCCAAUGUCUUUG

1659	177	AUGAUUGCUCUUGUUAAAGAA

1660	178	UGUGCGUCAUUCUCAGCUCUU

1661	179	UGAGGCAGGAACUUCUCAGAA

1662	180	UUCACCUCCUGGUACACGGGC

1663	181	UCCAGUAACACUUUAUGAUUG

1664	182	UCAAACUUGUUCACAUCAUUG

1665	183	UAACAGUGAUGACUUCCCUGC

1666	184	UAUCACAGUCAGAUCACCAUC

1667	185	UAGCAUACUUUGUUUGUUUGC

1668	186	AAGACUCUGAGAAGGUACGAU

1669	187	AACUUGUUCACAUCAUUGGAC

1670	188	AGCAUCUUGAUACACUGCUCU

1671	189	UUGCGCUGUGAUAUCUCAUCA

1672	190	UGGAGGUUGUUCACUUUCCUC

1673	191	UAUCUCAUCAAGUAGCAAAAA

1674	192	UGGUGAAGGUCACAAACACGA

1675	193	AAGAGGGUAACCGUCAGCCGC

1676	194	UAUCAGAAUCUGACUUGCAGC

1677	195	ACAUUUAGCAUACUUUGUUUG

1678	196	UAACAAGGACGUAGAAUACCA

1679	197	UUGCAGCUUUGAGGUACUGCA

1680	198	GUUAAGAUCUAGCUUCUCGGU

1681	199	AGGGUCUAGAAGAUUGUUGAG

1682	200	UAACUUCAUUCAUGGUCCUGA

1683	201	AUAAAUUCCUAAGUACCAGUU

1684	202	UUCCUUAGUGUGGGAGUUCCU

1685	203	AGAAUUGACUCAAACAUUUUG

1686	204	UGUUACUAAGACGAAGUGCCU

1687	205	AGUCACUGCAAUCGCCUGCAG

1688	206	AGGAAGUGUAAGAACACUGUC

1689	207	CUUGAUACACUGCUCUUGCAA

1690	208	UCGGUUACAUUUCCUCCUCCA

1691	209	UAGGGCAGUCACUGCAAUCGC

1692	210	UCAAAGAAUAAUACCGGAGCU

1693	211	UUCUUCCUAUUGGAUUUCUAU

1694	212	UCAGAAUUGACUCAAACAUUU

1695	213	UUGUUCACAUCAUUGGACAGC

1696	214	UAUUAUCCUUAUACCAGUUAU

1697	215	UUGAAGCACAUAGGCAACAUC

1698	216	UGCUAACUUCCGCAUCUACUG

1699	217	GUGAUGAGAACAACUUCCCAA

1700	218	UCUCCAAGGUGCUGUGAGCGG

1701	219	UAUCUCCAUCCAGAGUAGGGC

1702	220	UACCAUCUUUCAAUAUCAGAA

1703	221	UCGUCCAGGAGAUAGAUGUCA

1704	222	AUCCAAGUGUCCAAUGUCUUU

1705	223	AGCUUUGAGGUACUGCAACUG

1706	224	AUUGCCUCUGACACCCUCUCA

1707	225	CAGAAUCUUGGAAAUCUCCUU

1708	226	UCUCCUUCUUUCUCAAAUUGG

1709	227	ACUUCUUUAUCCCAGAACCCU

1710	228	ACUUUCCUCAUUAUCCUUCUU

1711	229	UACAUAUCAUCUUCCUCUAAU

1712	230	CUAACUUCCGCAUCUACUGCA

1713	231	UCGGAUGCUGACGAUUGCCUC

1714	232	AAUACACAGUUCGAACAAGUG

1715	233	AAGUUUGUGAAGAGUUAACAA

1716	234	UCAAAUUGGUAAUAAGAUUUG

1717	235	ACUUGCAGCUUUGAGGUACUG

1718	236	UUGCAAGGGCAGGAGAAUGAU

1719	237	GAUAUUCCUAUCUCCAUCCAG

1720	238	UCCUAUUGGAUUUCUAUCAAA

1721	239	UGGUACACGGGCAGCAUCUUG

1722	240	ACUGUCACCUGAUCAAACUUG

1723	241	UGGAAAUCUCCUUCUUUCUCA

1724	242	AGUUAAGAUCUAGCUUCUCGG

1725	243	AUUUCCAGUAACACUUUAUGA

1726	244	AUCAGAAUCUGACUUGCAGCU

1727	245	AAGAAGGCUUCUGUGCGUCAU

1728	246	ACCCUUGCAACUCCUCUCCAA

1729	247	UGACCAGCCCGUGACUUGGGG

1730	248	CUAAGUACCAGUUAAGAUCUA

1731	249	UUCCCGAGAACACCCAGGGCU

1732	250	UACUUUGUUUGUUUGCCCAGU

1733	251	AAUUCUUCCAUGCACGCUGAC

1734	252	UCAGUGAUGAGAACAACUUCC

1735	253	AUGACUUCCCUGCUCCCACGG

1736	254	AUUCUUCCUAUUGGAUUUCUA

1737	255	UUUCCUCAUUAUCCUUCUUUA

1738	256	UACCGGAGCUUUCAGAAUUGA

1739	257	AUAGGCAAUUCUUCCAUGCAC

1740	258	UUUCAAUAUCAGAAUCUGACU

1741	259	AGUUAUAACUUCAUUCAUGGU

1742	260	UUCGGAUGCUGACGAUUGCCU

1743	261	CAAGUGUCUGCUAACUUCCGC

1744	262	UCUGCUAACUUCCGCAUCUAC

1745	263	UGGGAGUUCCUGGAACUGGAG

1746	264	CUAUCAAAGAAUAAUACCGGA

1747	265	ACUUCCGCAUCUACUGCACUG

1748	266	UUCUCAAAUUGGUAAUAAGAU

1749	267	AUUGUUGAGACCAAACCGAAG

1750	268	CAAUCUUGAAGCACAUAGGCA

1751	269	UGUCCGCUCGGCUGGAGCCUG

1752	270	AGGAGGGUCUAGAAGAUUGUU

1753	271	UGCUCUUGUUAAAGAAGGCUU

1754	272	UUUGUUUGUUUGCCCAGUAUG

1755	273	UUCCUAAGUACCAGUUAAGAU

1756	274	UCUCCUAUCACAGUCAGAUCA

1757	275	UCACAUCAUUGGACAGCAGAU

1758	276	UACCAGUUAUAACUUCAUUCA

1759	277	UUACAGUGACAUUUAGCAUAC

1760	278	UGACUUCCCUGCUCCCACGGG

1761	279	UAGCUUCUCGGUUACAUUUCC

1762	280	AAAUUGGUAAUAAGAUUUGAA

1763	281	ACAGUGACAUUUAGCAUACUU

1764	282	CAAGUGUCCAAUGUCUUUGGA

1765	283	AGAGUUAACAAGGACGUAGAA

1766	284	GUACCAGUUAAGAUCUAGCUU

1767	285	AUUGGACAGCAGAUUGACUAU

1768	286	AGAAUCUGACUUGCAGCUUUG

1769	287	UGGAUUUCUAUCAAAGAAUAA

1770	288	AGAAUACCAAUAGAGAUCUUG

1771	289	UGAAUAAAUUCCUAAGUACCA

1772	290	AUCAAACUUGUUCACAUCAUU

1773	291	AUCAUUGGACAGCAGAUUGAC

1774	292	UCAGCGGCAGCAAAUCAUCCA

1775	293	AGUGACAUUUAGCAUACUUUG

1776	294	CACUUUAUGAUUGCUCUUGUU

1777	295	UAGAUGUCAGCAUCUUGAUAC

1778	296	CAUCUUCCUCUAAUCUCCGUU

1779	297	CUGAAUACAUAUCAUCUUCCU

1780	298	ACAGUGAUGACUUCCCUGCUC

1781	299	UUAUCCUUAUACCAGUUAUAA

1782	300	UCCUUAUACCAGUUAUAACUU

1783	301	UGUUGUGCAAAGUUUGUGAAG

1784	302	UGACUUGCAGCUUUGAGGUAC

1785	303	ACUGCAACUGAUGAGUCACUA

1786	304	ACACGGGCAGCAUCUUGCCGG

1787	305	UGUUUGUUUGCCCAGUAUGAA

1788	306	AUUUGACAAAUACACAGUUCG

1789	307	UUCGCGUCCUGCAGCGGGUUG

1790	308	UUAUGAUUGCUCUUGUUAAAG

1791	309	UCUGUGCGUCAUUCUCAGCUC

1792	310	AAGGUCACAAACACGAUGAUU

1793	311	UUCCUCCUCCAUUUACAGUGA

1794	312	UCUCAGAAUCUUGGAAAUCUC

1795	313	UGAUACACUGCUCUUGCAAGG

1796	314	UUGUUGAGACCAAACCGAAGA

1797	315	AUUGUGAUCUUCUCAUGCAAA

1798	316	AGAGUUCCCGAGAACACCCAG

1799	317	ACAGGAAGUGUAAGAACACUG

1800	318	AAGAACACUGUCACCUGAUCA

1801	319	UUACUAAGACGAAGUGCCUCA

1802	320	AUCUCCUUCUUUCUCAAAUUG

1803	321	ACACAGUUCGAACAAGUGUCU

1804	322	AUCUUCCUCUAAUCUCCGUUU

1805	323	UCACCUGAUCAAACUUGUUCA

1806	324	UACUGCAACUGAUGAGUCACU

1807	325	UCAAGGAGGGUCUAGAAGAUU

1808	326	UGAGAGGAUCGUCCAGGAGAU

1809	327	AGUGUAAGAACACUGUCACCU

1810	328	UCCUCCUCCAUUUACAGUGAC

1811	329	UAGCUACAGUUAAACCUGAAU

1812	330	UGAGAAGGUACGAUUCCUUAG

1813	331	UUCUUUCUCAAAUUGGUAAUA

1814	332	UCCAGAGUAGGGCAGUCACUG

1815	333	AAAGGCCUUGUAGAGUUGGGG

1816	334	UUAACAAGGACGUAGAAUACC

1817	335	UUGGAUUUCUAUCAAAGAAUA

1818	336	UGCUUUCUGCCCUCCACUCAG

1819	337	UUGUUUGUUUGCCCAGUAUGA

1820	338	UUCAUCCCUCUGAGGCAGGAA

1821	339	AGAAUCUUGGAAAUCUCCUUC

1822	340	UACCAUCUGACGGCAGCUGAC

1823	341	AUUACUCCUCAGAGUUCCCGA

1824	342	GAGAAUGAUUAGAACUGCCAU

1825	343	ACGUAGAAUACCAAUAGAGAU

1826	344	UUGUGAUCUUCUCAUGCAAAA

1827	345	UACAUUUCCUCCUCCAUUUAC

1828	346	UGAUCAAACUUGUUCACAUCA

1829	347	GAACUUCUCAGAAUCUUGGAA

1830	348	UUCCUCUAAUCUCCGUUUAUG

1831	349	UAGGCAAUUCUUCCAUGCACG

1832	350	UGUGGGAGUUCCUGGAACUGG

1833	351	AUCUCCAUCCAGAGUAGGGCA

1834	352	AUUCCUAUCUCCAUCCAGAGU

1835	353	UGAAGGUCACAAACACGAUGA

1836	354	UCACUUUCCUCAUUAUCCUUC

1837	355	AAGUGUAAGAACACUGUCACC

1838	356	AGAACACUGUCACCUGAUCAA

1839	357	AACUUCAUUCAUGGUCCUGAU

1840	358	AAGGUUUACCCGUGCUUUCUG

1841	359	UCACUGCAAUCGCCUGCAGUG

1842	360	UCGCCUGCAGUGGUCCUGCCC

1843	361	UCCGCAUCUACUGCACUGAGA

1844	362	UGAGACCAAACCGAAGACUCU

1845	363	UCUUUCAAGGAGGGUCUAGAA

1846	364	AGCUUCUCGGUUACAUUUCCU

1847	365	AACAAGUGUCUGCUAACUUCC

1848	366	GUGUAAGAACACUGUCACCUG

1849	367	CUUUGAGGUACUGCAACUGAU

1850	368	UGAAGCACAUAGGCAACAUCU

1851	369	UUCUUCCAUGCACGCUGACCA

1852	370	AAUAAUACCGGAGCUUUCAGA

1853	371	CAGAUCACCAUCCUCCAACAG

1854	372	UUGAGACCAAACCGAAGACUC

1855	373	AAGAUCUAGCUUCUCGGUUAC

1856	374	AGGAACUUCUCAGAAUCUUGG

1857	375	UCAUCCAAGUGUCCAAUGUCU

1858	376	AUGUCUUUGGAGAAACGAUUU

1859	377	AGGAACUCAGUGUAAGUCCCC

1860	378	CAAAGAAUAAUACCGGAGCUU

1861	379	UGGAACUGGAGGUUGUUCACU

1862	380	AGCACAUAGGCAACAUCUUGG

1863	381	ACGAUUGCCUCUGACACCCUC

1864	382	UGAUGAGAACAACUUCCCAAA

1865	383	UUGGUAAUAAGAUUUGAAAAU

1866	384	UAAUACCGGAGCUUUCAGAAU

1867	385	CAAUCGCCUGCAGUGGUCCUG

1868	386	UGCAAAGUUUGUGAAGAGUUA

1869	387	AAGAACACGCGUGAGCAGAGG

1870	388	UCCUAUCUCCAUCCAGAGUAG

1871	389	AACUUCCGCAUCUACUGCACU

1872	390	AGAAGGUACGAUUCCUUAGUG

1873	391	UGCAACUGAUGAGUCACUAAA

1874	392	UGUCUGCUAACUUCCGCAUCU

1875	393	UCACACUGCCGAGGAGCACGU

1876	394	AUGCUGACGAUUGCCUCUGAC

1877	395	GUCUGCUAACUUCCGCAUCUA

1878	396	CAUACUUUGUUUGUUUGCCCA

1879	397	AGUAACACUUUAUGAUUGCUC

1880	398	GAAUAAAUUCCUAAGUACCAG

1881	399	UCUGGAUUCUUCGGAUGCUGA

1882	400	GACAGCAGAUUGACUAUCUGG

1883	401	CUCCAGAGCACCAUCUUUCAA

1884	402	CAGAAGAACACGCGUGAGCAG

1885	403	GUUCACAUCAUUGGACAGCAG

1886	404	UCUCAAAUUGGUAAUAAGAUU

1887	405	UCUGACGGCAGCUGACGGUUG

1888	406	UUGUUCACUUUCCUCAUUAUC

1889	407	AGCACGGCACUUAACAGUGAU

1890	408	GUAGCUACAGUUAAACCUGAA

1891	409	UUUGCCCAGUAUGAAAGCCAC

1892	410	UGGUCCUGCCCACAGGAAGUG

1893	411	AGUUUGUGAAGAGUUAACAAG

1894	412	GAUUGUUGAGACCAAACCGAA

1895	413	CCACAGCUAACAAUUCGCCAG

1896	414	AUCCCUCUGAGGCAGGAACUU

1897	415	CACAGUCAGAUCACCAUCCUC

1898	416	AACUCCUCUCCAAGGUGCUGU

1899	417	UCGAACAAGUGUCUGCUAACU

1900	418	UCUGACAGUAAAGGAAAGGCC

1901	419	UUGGGCUUCACCUCCUGGUAC

1902	420	AUUCUUCGGAUGCUGACGAUU

1903	421	GCACUGAAUACAUAUCAUCUU

1904	422	UAAGACGAAGUGCCUCAAUUA

1905	423	AAUGUCUUUGGAGAAACGAUU

1906	424	CUUGUUCACAUCAUUGGACAG

1907	425	AUCAUCCAAGUGUCCAAUGUC

1908	426	UAAGAACACUGUCACCUGAUC

1909	427	AUCUGACGGCAGCUGACGGUU

1910	428	AGGAUCGUCCAGGAGAUAGAU

1911	429	CAGAAUCUGACUUGCAGCUUU

1912	430	AGCACAAGCCUUUAUGACUUU

1913	431	GAGCUUUCAGAAUUGACUCAA

1914	432	AUCCGUGAAAGUUGCAGUUUU

1915	433	UCCAGGAGAUAGAUGUCAGCA

1916	434	ACACUUUAUGAUUGCUCUUGU

1917	435	UGCAAGGUUUACCCGUGCUUU

1918	436	UGGACCUCAAGCAGGGAUGCU

1919	437	AAAUUCCUAAGUACCAGUUAA

1920	438	GAGACCAAACCGAAGACUCUG

1921	439	ACUUUAUGAUUGCUCUUGUUA

1922	440	UCCUCUCCAAGGUGCUGUGAG

1923	441	AGGUUCGCGUCCUGCAGCGGG

1924	442	UACAGUUAAACCUGAAUAAAU

1925	443	CAGAGCACCAUCUUUCAAGGA

1926	444	ACGGUAGCUACAGUUAAACCU

1927	445	AAGGUACGAUUCCUUAGUGUG

1928	446	AACUUCUCAGAAUCUUGGAAA

1929	447	CUCAGUGAUGAGAACAACUUC

1930	448	CACACUGCCGAGGAGCACGUA

1931	449	AUCUGACUUGCAGCUUUGAGG

1932	450	GAUUCUUCGGAUGCUGACGAU

1933	451	ACUGCAAUCGCCUGCAGUGGU

1934	452	UCCUCCAUUUACAGUGACAUU

1935	453	CAACUCCUCUCCAAGGUGCUG

1936	454	UUCUUCGGAUGCUGACGAUUG

1937	455	AAACCGAAGACUCUGAGAAGG

1938	456	CAGCAUCUUGAUACACUGCUC

1939	457	UCUCCAGAGCACCAUCUUUCA

1940	458	CAAACUUGUUCACAUCAUUGG

1941	459	AGAGUAGGGCAGUCACUGCAA

1942	460	UCUUGGAAAUCUCCUUCUUUC

1943	461	UUUCUAUCAAAGAAUAAUACC

1944	462	UCACCUCCUGGUACACGGGCA

1945	463	AUCUACUGCACUGAGAGGAUC

1946	464	UCCGCUCGGCUGGAGCCUGUG

1947	465	AUCUUGAUACACUGCUCUUGC

1948	466	GUUCGAACAAGUGUCUGCUAA

1949	467	AUUUCCUCCUCCAUUUACAGU

1950	468	UCUUGAAGCACAUAGGCAACA

1951	469	UCCGUGAAAGUUGCAGUUUUA

1952	470	UGACGGCAGCUGACGGUUGCG

1953	471	UCCUGGACCUCAAGCAGGGAU

1954	472	CAUCUGACGGCAGCUGACGGU

1955	473	AAGGAGGGUCUAGAAGAUUGU

1956	474	CUUCUUUAUCCCAGAACCCUU

1957	475	UCCAGAGCACCAUCUUUCAAG

1958	476	ACCGAAGACUCUGAGAAGGUA

1959	477	AAUCAUCCAAGUGUCCAAUGU

1960	478	AAUAAGAUUUCCAGUAACACU

1961	479	CUAGAAGAUUGUUGAGACCAA

1962	480	AAGGACGUAGAAUACCAAUAG

1963	481	UCUUUCUCAAAUUGGUAAUAA

1964	482	UCUCUGAUGCCUUAUCCCAAA

1965	483	UCCAUGCACGCUGACCAGCCC

1966	484	AUUGCUCUUGUUAAAGAAGGC

1967	485	GGAACUUCUCAGAAUCUUGGA

1968	486	UGCGUCAUUCUCAGCUCUUAA

1969	487	UUUCUCAAAUUGGUAAUAAGA

1970	488	AUCGUCCAGGAGAUAGAUGUC

1971	489	UGCAGUGGUCCUGCCCACAGG

1972	490	GUCUGGAUUCUUCGGAUGCUG

1973	491	UGACGAUUGCCUCUGACACCC

1974	492	AAUAAAUUCCUAAGUACCAGU

1975	493	AGCACCAUCUUUCAAGGAGGG

1976	494	GUAAGAACACUGUCACCUGAU

1977	495	UCUUGCAAGGUUUACCCGUGC

1978	496	AGGUUGUUCACUUUCCUCAUU

1979	497	GCAUCUUGAUACACUGCUCUU

1980	498	ACAGUUCGAACAAGUGUCUGC

1981	499	AGCAAAUCAUCCAAGUGUCCA

1982	500	UAGGUGGUGAAGGUCACAAAC

1983	501	CAGAGUUCCCGAGAACACCCA

1984	502	UGUUGAGACCAAACCGAAGAC

1985	503	ACCAAUAGAGAUCUUGCUAUG

1986	504	CAGUUCGAACAAGUGUCUGCU

1987	505	AAAGAAUAAUACCGGAGCUUU

1988	506	UGGAUUCUUCGGAUGCUGACG

1989	507	AUCUAGCUUCUCGGUUACAUU

1990	508	AUAAUACCGGAGCUUUCAGAA

1991	509	GUGACAUUUAGCAUACUUUGU

1992	510	UCAUUGGACAGCAGAUUGACU

1993	511	CUGCACUGAGAGGAUCGUCCA

1994	512	UAUGAUUGCUCUUGUUAAAGA

1995	513	AUCUUGAAGCACAUAGGCAAC

1996	514	UCUACUGCACUGAGAGGAUCG

1997	515	UGUCCAAUGUCUUUGGAGAAA

1998	516	AGUACCAGUUAAGAUCUAGCU

1999	517	CUUAGUGUGGGAGUUCCUGGA

2000	518	UGAUUGCUCUUGUUAAAGAAG

2001	519	CAAAUUGGUAAUAAGAUUUGA

2002	520	GAUAGAUGUCAGCAUCUUGAU

2003	521	UACUCCUCAGAGUUCCCGAGA

2004	522	UCUUCGGAUGCUGACGAUUGC

2005	523	GAAGCACAUAGGCAACAUCUU

2006	524	GAAGACUCUGAGAAGGUACGA

2007	525	CUGUGCGUCAUUCUCAGCUCU

2008	526	AGAGCACCAUCUUUCAAGGAG

2009	527	GACAUUUAGCAUACUUUGUUU

2010	528	CUGCCGAGGAGCACGUAGGUG

2011	529	CUCCAACAGCUGUAAAUCCUU

2012	530	AUUGGUAAUAAGAUUUGAAAA

2013	531	CAGAAUUGACUCAAACAUUUU

2014	532	CUAUCACAGUCAGAUCACCAU

2015	533	CUGUGAUAUCUCAUCAAGUAG

2016	534	AGAUAGAUGUCAGCAUCUUGA

2017	535	AUUAUCCUUAUACCAGUUAUA

2018	536	AGAACCCUUGCAACUCCUCUC

2019	537	AUACCGGAGCUUUCAGAAUUG

2020	538	ACGCGUGAGCAGAGGUUCGCG

2021	539	ACAAGGACGUAGAAUACCAAU

2022	540	GUGAAGGUCACAAACACGAUG

2023	541	AAGGCCUUGUAGAGUUGGGGU

2024	542	AACCGUCAGCCGCACAGCCCC

2025	543	GAGAUAGAUGUCAGCAUCUUG

2026	544	AAACCUGAAUAAAUUCCUAAG

2027	545	ACGAAGUGCCUCAAUUAACGU

2028	546	UCGUAUUUCUUCCCAAAUAAA

2029	547	UCGCGCUGAUCAGGCGGCGGU

2030	548	UGCUGAGACACAUAGGCAAUU

2031	549	AGAGGGUAACCGUCAGCCGCA

2032	550	GAUCAAACUUGUUCACAUCAU

2033	551	UGUGCAAAGUUUGUGAAGAGU

2034	552	CAGCAAGGCACGAUAUUCCUA

2035	553	UUAUAACUUCAUUCAUGGUCC

2036	554	UUCGAACAAGUGUCUGCUAAC

2037	555	UUUCAAGGAGGGUCUAGAAGA

2038	556	ACAGCUUUGCAAGGGCAGGAG

2039	557	GUGAUGACUUCCCUGCUCCCA

2040	558	UAGUGUGGGAGUUCCUGGAAC

2041	559	UGUGAAGAGUUAACAAGGACG

2042	560	CAAAUACACAGUUCGAACAAG

2043	561	AUACCAGUUAUAACUUCAUUC

2044	562	AUAUUCCUAUCUCCAUCCAGA

2045	563	AAGAAGAGGGUAACCGUCAGC

2046	564	UGCAACUCCUCUCCAAGGUGC

2047	565	GUUACUAAGACGAAGUGCCUC

2048	566	ACGCCUGUCCGCUCGGCUGGA

2049	567	CAUCCAAGUGUCCAAUGUCUU

2050	568	ACCGUCAGCCGCACAGCCCCA

2051	569	CAUUGGACAGCAGAUUGACUA

2052	570	UGUUCACAUCAUUGGACAGCA

2053	571	ACCUGAAUAAAUUCCUAAGUA

2054	572	AUUGGAUUUCUAUCAAAGAAU

2055	573	UUUGUUUGCCCAGUAUGAAAG

2056	574	CAAGGUGCUGUGAGCGGUCUU

2057	575	AACUGGAGGUUGUUCACUUUC

2058	576	GUGCUGUGAGCGGUCUUCUGG

2059	577	CUACUGCACUGAGAGGAUCGU

2060	578	UCCCGAGAACACCCAGGGCUG

2061	579	AACCGAAGACUCUGAGAAGGU

2062	580	AAAUACACAGUUCGAACAAGU

2063	581	UUCUCAGAAUCUUGGAAAUCU

2064	582	AUUCAUCCCUCUGAGGCAGGA

2065	583	ACCUCAAGCAGGGAUGCUGGG

2066	584	GACACAUAGGCAAUUCUUCCA

2067	585	UCAGAGCACAAGCCUUUAUGA

2068	586	ACUAAAUAAGAUUUCCAGUAA

2069	587	AGUUCCUGGAACUGGAGGUUG

2070	588	CAGAGUAGGGCAGUCACUGCA

2071	589	GUCUCUGAUGCCUUAUCCCAA

2072	590	CAUCUUUCAAGGAGGGUCUAG

2073	591	CCAUCUUUCAAGGAGGGUCUA

2074	592	UACUCCUCAGUGAUGAGAACA

2075	593	AACCUGAAUAAAUUCCUAAGU

2076	594	AUUUCUAUCAAAGAAUAAUAC

2077	595	CGGUAGCUACAGUUAAACCUG

2078	596	GAAGAAGAGGGUAACCGUCAG

2079	597	UCCAAGGUGCUGUGAGCGGUC

2080	598	UGUUAAAGAAGGCUUCUGUGC

2081	599	ACGCUGACCAGCCCGUGACUU

2082	600	AAGACGAAGUGCCUCAAUUAA

2083	601	AGGACGUAGAAUACCAAUAGA

2084	602	UAUCCUUAUACCAGUUAUAAC

2085	603	GCUGCUGAGACACAUAGGCAA

2086	604	CACCUGAUCAAACUUGUUCAC

2087	605	GAGGUUCGCGUCCUGCAGCGG

2088	606	UGUGAUAUCUCAUCAAGUAGC

2089	607	CACUGUCACCUGAUCAAACUU

2090	608	CUUUCCUCAUUAUCCUUCUUU

2091	609	UCCACUCAGCGUGGUUCCCCG

2092	610	AGAGGUUCGCGUCCUGCAGCG

2093	611	CUUCCGCAUCUACUGCACUGA

2094	612	GUCACAAACACGAUGAUUUUG

2095	613	CCAAUCUUGAAGCACAUAGGC

2096	614	CACUGAAUACAUAUCAUCUUC

2097	615	ACCAGUUAAGAUCUAGCUUCU

2098	616	AGGGCAGUCACUGCAAUCGCC

2099	617	AAAUAAGAUUUCCAGUAACAC

2100	618	AGCACGUAGGUGGUGAAGGUC

2101	619	GAAUCUGACUUGCAGCUUUGA

2102	620	GUCAGCAUCUUGAUACACUGC

2103	621	AAGAAUAAUACCGGAGCUUUC

2104	622	AGAUUUCCAGUAACACUUUAU

2105	623	ACAUCAUUGGACAGCAGAUUG

2106	624	UCCUCUAAUCUCCGUUUAUGG

2107	625	AGACCAAACCGAAGACUCUGA

2108	626	CUUCACCUCCUGGUACACGGG

2109	627	UUUGGAGAAACGAUUUAAAAU

2110	628	UCGCGUCCUGCAGCGGGUUGG

2111	629	ACUGCCGAGGAGCACGUAGGU

2112	630	AGGUACGAUUCCUUAGUGUGG

2113	631	CUUGCAACUCCUCUCCAAGGU

2114	632	UCUUUAUCCCAGAACCCUUGC

2115	633	GAAGUGUAAGAACACUGUCAC

2116	634	CUGGAGGUUGUUCACUUUCCU

2117	635	UAUCCCAGAACCCUUGCAACU

2118	636	GGUAGCUACAGUUAAACCUGA

2119	637	AUGUCAGCAUCUUGAUACACU

2120	638	CCAGUUAAGAUCUAGCUUCUC

2121	639	CUCCAAGGUGCUGUGAGCGGU

2122	640	CAGUAACACUUUAUGAUUGCU

2123	641	AUCCAGAGUAGGGCAGUCACU

2124	642	GUGAAGAGUUAACAAGGACGU

2125	643	GGACAGCAGAUUGACUAUCUG

2126	644	GUGAGCAGAGGUUCGCGUCCU

2127	645	CUCUGAGGCAGGAACUUCUCA

2128	646	CAAUUCUUCCAUGCACGCUGA

2129	647	GAAGGUCACAAACACGAUGAU

2130	648	AGGAGAAUGAUUAGAACUGCC

2131	649	CAGGAAGUGUAAGAACACUGU

2132	650	AGAAGAACACGCGUGAGCAGA

2133	651	GAACUGGAGGUUGUUCACUUU

2134	652	CGAAGUGCCUCAAUUAACGUA

2135	653	ACCAUCCUCCAACAGCUGUAA

2136	654	CAUCCGUGAAAGUUGCAGUUU

2137	655	AUCGCCUGCAGUGGUCCUGCC

2138	656	CCGAGGAGCACGUAGGUGGUG

2139	657	CUGCACAUGCACCAUCUUUUU

2140	658	ACUUUGUUUGUUUGCCCAGUA

2141	659	GAUGUCAGCAUCUUGAUACAC

2142	660	GAGGUUGUUCACUUUCCUCAU

2143	661	UUAUCCCAGAACCCUUGCAAC

2144	662	AAUUGGUAAUAAGAUUUGAAA

2145	663	UCCUAUCACAGUCAGAUCACC

2146	664	CUGACAGUAAAGGAAAGGCCU

2147	665	CAUCAUUGGACAGCAGAUUGA

2148	666	ACCAAUCUUGAAGCACAUAGG

2149	667	AGAUCUAGCUUCUCGGUUACA

2150	668	UACCCGUGCUUUCUGCCCUCC

2151	669	CUGUCCGCUCGGCUGGAGCCU

2152	670	AAGGUGCUGUGAGCGGUCUUC

2153	671	AAUUCCUAAGUACCAGUUAAG

2154	672	ACUGAAUACAUAUCAUCUUCC

2155	673	GCUCUUGCAAGGUUUACCCGU

2156	674	GAAUACAUAUCAUCUUCCUCU

2157	675	UCUGCCCUCCACUCAGCGUGG

2158	676	UCUUCCUAUUGGAUUUCUAUC

2159	677	UGGACAGCAGAUUGACUAUCU

2160	678	CAAUGUCUUUGGAGAAACGAU

2161	679	UUCCAUGCACGCUGACCAGCC

2162	680	AGAACACCCAGGGCUGCUGAG

2163	681	UGUGAUCUUCUCAUGCAAAAU

2164	682	ACGGGCAGCAUCUUGCCGGGC

2165	683	GAACAAGUGUCUGCUAACUUC

2166	684	UGCCUCUGACACCCUCUCAAU

2167	685	CCAUGCACGCUGACCAGCCCG

2168	686	AAGGAAAGGCCUUGUAGAGUU

2169	687	CACCAUCCUCCAACAGCUGUA

2170	688	CGAACAAGUGUCUGCUAACUU

2171	689	GAAGAGGGUAACCGUCAGCCG

2172	690	ACUCCUCUCCAAGGUGCUGUG

2173	691	GAAUCUUGGAAAUCUCCUUCU

2174	692	CAGCGGCAGCAAAUCAUCCAA

2175	693	AAGGGCAGGAGAAUGAUUAGA

2176	694	AUAUCUCAUCAAGUAGCAAAA

2177	695	UUUGCAAGGGCAGGAGAAUGA

2178	696	AAAUCAUCCAAGUGUCCAAUG

2179	697	CGAUAUUCCUAUCUCCAUCCA

2180	698	UAAAUAAGAUUUCCAGUAACA

2181	699	CUUGAAGCACAUAGGCAACAU

2182	700	AGGAAAGGCCUUGUAGAGUUG

2183	701	UGCACGCUGACCAGCCCGUGA

2184	702	UCCCUCUGAGGCAGGAACUUC

2185	703	ACACUGCUCUUGCAAGGUUUA

2186	704	CAGGAGAAUGAUUAGAACUGC

2187	705	CACAUAGGCAAUUCUUCCAUG

2188	706	GCAUCUACUGCACUGAGAGGA

2189	707	CACUGCAAUCGCCUGCAGUGG

2190	708	GAACACUGUCACCUGAUCAAA

2191	709	AAGGCUUCUGUGCGUCAUUCU

2192	710	GUGUCCAAUGUCUUUGGAGAA

2193	711	AUCCCAGAACCCUUGCAACUC

2194	712	UCAGAGUUCCCGAGAACACCC

2195	713	CCAAUGUCUUUGGAGAAACGA

2196	714	ACGUCAGCGGCAGCAAAUCAU

2197	715	AGAACGGUAGCUACAGUUAAA

2198	716	GACCAAACCGAAGACUCUGAG

2199	717	GAACACGCGUGAGCAGAGGUU

2200	718	CUCUUGCAAGGUUUACCCGUG

2201	719	CAGUGAUGAGAACAACUUCCC

2202	720	AACACGCGUGAGCAGAGGUUC

2203	721	GUGAUAUCUCAUCAAGUAGCA

2204	722	GCAGGAACUUCUCAGAAUCUU

2205	723	CUUUAUCCCAGAACCCUUGCA

2206	724	ACCAUCUUUCAAUAUCAGAAU

2207	725	ACCUGAUCAAACUUGUUCACA

2208	726	AAUACCGGAGCUUUCAGAAUU

TABLE 6

Results for PAK3. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_	siRNA guide strand/
NO	id	AS Sequence

2209	1	UAUAUCUCUAUGGAUCACCUG

2210	2	UUAUCUUGCAAGUUCAACCCA

2211	3	UUAGGUAUCAUUAUCUUUGUU

2212	4	UAAUGUAUCUAUUUCCUCCUG

2213	5	UAAUUUGUCAACAUUUCUCAA

2214	6	UUUACAAUGACACACACACGA

2215	7	UUCUGUAUUGAGAAUGACCAA

2216	8	AUUAAGGAGAUUAACAACCUG

2217	9	UCUAAUAGUGACAUCUCCCUA

2218	10	UUAAUAUUAAACACAUUCCCA

2219	11	UUACAAUGACACACACACGAG

2220	12	UAAAUAAUCUCUACUGUGCUU

2221	13	UUAACUGAAUAUUAACUGCAA

2222	14	UUCAUUAAUAAUUAAUUCCUU

2223	15	UUCUCUACUAUCGCUGUUGAU

2224	16	ACAACUACUGCAAACAACCUA

2225	17	UUGAGUGCUGAAGAAUCCCGG

2226	18	UAAUAUUAAACACAUUCCCAA

2227	19	AUGAUAUACAGUAAUAUCCUG

2228	20	UAUCUUGCAAGUUCAACCCAA

2229	21	UCAUUCUCUACUAUCGCUGUU

2230	22	UUCAGAACCUGAACUCACCUA

2231	23	UUCCUGAACACACAUAUUCCU

2232	24	UAUACAGACAACAGGAAGCAA

2233	25	UUAUGGGAUAGCAUUUGCCUG

2234	26	UUGCUGUUGAAGGUUCAUCUG

2235	27	UUUACAGAUAACACAUUCUGA

2236	28	UAUAGAAUCUCUCAGAACUGG

2237	29	UUAGAGAAACAACUUUCUGUA

2238	30	UAAGUGUUUAGGUUCACUCUU

2239	31	UGAUAUUAUAGAAUCUCUCAG

2240	32	UUAAUAAUUAAUUCCUUCUUG

2241	33	UAUUAUUAUCAAAUCUUGGUA

2242	34	UACUAUAUCACCUUUCUCUAG

2243	35	UUGAGUUAAAUCUUCUUACAU

2244	36	UAGAAUACUCGUACACACAGG

2245	37	UUUACAUACAGACUGUAUGGA

2246	38	UAUUAUGAACUUCAUUUGCUU

2247	39	UUUGGUUAGAUGGUCUCCCUU

2248	40	UUUGCAAUACUUUAGGUCCAA

2249	41	UUCUAAUAGUGACAUCUCCCU

2250	42	UUAUAGAAUCUCUCAGAACUG

2251	43	UUUCUUACAGAGUUGAAUGUU

2252	44	UAAGGCUUGCAGUCUUAGCGG

2253	45	UAUAGUUUGCUGAAACUCUAA

2254	46	UUGCCUAGCGUCACAUAGCAA

2255	47	UAACUUAUAGAUAAUAGUCUC

2256	48	UUAUAGAUAAUAGUCUCCUAA

2257	49	AUUAACAGAACUAUAACUGAA

2258	50	UAAAUAAAUAAUCUCUACUGU

2259	51	UAAAUUACAUAAUCUGAGGGA

2260	52	AAGUUGUAUAGAAUACUCGUA

2261	53	UUUAAUAUUAAACACAUUCCC

2262	54	UAGAGAAACAACUUUCUGUAA

2263	55	UAUAAUUAUUUACACGAUCUU

2264	56	UGUAACUAGCAAAUAUCUCUG

2265	57	UAGACAAAUAUCUCAAACUAU

2266	58	AUUUACACGAUCUUUGAGCUG

2267	59	AUAAUUAACAAUAUUAGGGUU

2268	60	UUGUUGACUGUUUCUUUGGAA

2269	61	UUGGGUACUAAAUCUGUUGAA

2270	62	UUAAUUUGUCAACAUUUCUCA

2271	63	UCUACUGUGCUUCUCACCCUU

2272	64	UAUAUUAUUAUCAAAUCUUGG

2273	65	UAAUUUAGGUAUCAUUAUCUU

2274	66	UUACUAUUCAUCCUCAGUGGA

2275	67	UUAAGGAGAUUAACAACCUGG

2276	68	UUUGAGAACAUCUAGAACAGC

2277	69	UACAGAUGAGGAAACAGCCAU

2278	70	UUAAUGUAUCUAUUUCCUCCU

2279	71	UGGAAUAAUUGUAACUAGCAA

2280	72	UUCUAUAACACAAAUUGUUAG

2281	73	UAACUGAAUAUUAACUGCAAG

2282	74	AAGACCAAGAGAUUCAACCGG

2283	75	UUAACAACCUGGUUUACUCAA

2284	76	UUCUCUAUGUUGGUCAGGCUG

2285	77	UAUUUCUGGUUGUUGACUGUU

2286	78	AAUAUUAACUGCAAGUAGCUU

2287	79	UAUUGCUUCAACCACAAUUUA

2288	80	UUUAUUUAGAUAUACAGUUUU

2289	81	UUAACUGCAAGUAGCUUAGAU

2290	82	AUAGAAUUUGAGAACAUCUAG

2291	83	UUUCAUAGGAGAAAUAUUCCA

2292	84	UUGUUUAAUAUUAAACACAUU

2293	85	UUAACUUAUAGAUAAUAGUCU

2294	86	UAUCGCUGUUGAUUUCCUCUU

2295	87	UUACUAUAUCACCUUUCUCUA

2296	88	UAGUGCUUCGUUUACUUUGCU

2297	89	UAUAGCAGGCUGAAUUUGCAA

2298	90	UUUGGAAUCAUAGAAUUUGAG

2299	91	UACUUGAGUUAAAUCUUCUUA

2300	92	UACAUAGUUGUAAUCCCUGUU

2301	93	UACACUAUAUAGUUUGCUGAA

2302	94	AAUCUGUUGAACAUGUUGCCA

2303	95	UUGUCCUGUUGCAAUGUCUAG

2304	96	UAUCUCAGGGCACACUAGCAA

2305	97	UCUAGCAAGUGUGACAGUGUG

2306	98	UAAAGCUCAUAUUAGACUCCG

2307	99	UUAUAUUCUAGCAAGUGUGAC

2308	100	UUACCCAACAUGGUGACUGAU

2309	101	UAUUUCAGUCUUACUCAUGAG

2310	102	UCUCCUGAACAUAAACACGUA

2311	103	UUAGAUGGAUGGAUGUACCUU

2312	104	UUCCUUUGCAGCGAUAAUCAG

2313	105	UAUGACAACGCACUGGAUCCU

2314	106	UUACUUAAUGUCCAACAAGGA

2315	107	UCUCUCUGCAACUUGUAAGUG

2316	108	UAUGCUCUGGUCUUGGUGCGA

2317	109	UUGUAUAGAAUACUCGUACAC

2318	110	UUGCUCUGGAAUUCCAGUGAA

2319	111	UAGAAUUUGAGAACAUCUAGA

2320	112	UUAUUUGGUACUGCUGGUGAA

2321	113	AUUAUUUACACGAUCUUUGAG

2322	114	UAAUUGCUUCCUUUGCAGCGA

2323	115	AUAAAUUACAUAAUCUGAGGG

2324	116	UUAAACACAUUCCCAAUGCAU

2325	117	UUUCUUAUUCUUCUCUUCAGG

2326	118	AUUUCCUAGGUUCAGAACCUG

2327	119	AUGAGAAACAGCUUCUUUCUA

2328	120	UUCUCCUAUGAGGAUUUCCUA

2329	121	UUCUCCUUCUUCUUAUUGGUU

2330	122	UAUCCCACUACAUCUGACUCA

2331	123	UUAGCUUCUCUAAGAUCUCCU

2332	124	UGGAAGUUUGGAGUAAUCGUG

2333	125	UAUAGUUCCCUUUCUGCUGUU

2334	126	UUACAGAUAACACAUUCUGAC

2335	127	UUACUCAUGAGGGAGAUGGUG

2336	128	UCAUCUAGUCCAAUACACUUA

2337	129	UUGUCACUCUUUAUAUCUCUA

2338	130	UUCAGUCUUACUCAUGAGGGA

2339	131	UAUCUGAGGUGACUACCUCAU

2340	132	UAGAACAGCUUGUGGGUUCUU

2341	133	UAUUUAUCCCACUACAUCUGA

2342	134	UAAGAUCUCCUCAUCUGUCAU

2343	135	UAGUCCAAUACACUUAUUUUA

2344	136	UUACAUACAGACUGUAUGGAA

2345	137	UGAGAACAUCUAGAACAGCUU

2346	138	AUAAGUUCUGUUUAGAUUCUU

2347	139	UACUCGAUUGUACCAAAUGUG

2348	140	UAACAUAAAGAAUAAAUACUU

2349	141	UUGUACCAAAUGUGAAUCCUU

2350	142	UCUUAUUCUUCUCUUCAGGGG

2351	143	UUCUCUGCCUACAGUGAUCUG

2352	144	UAUAACACAAAUUGUUAGUUU

2353	145	UUAAGUGACUUGCCUAGCGUC

2354	146	UUUAGGUUCACUCUUAGCAGU

2355	147	UAUUAUUAUGAACUUCAUUUG

2356	148	AUAGGUACACAAACCAAGCCA

2357	149	AAGAAUUUCACUACACAUGGU

2358	150	UACAAUGACACACACACGAGA

2359	151	AAGUAUUCCAUGACUACCCAU

2360	152	UAUCUCUAUGGAUCACCUGGU

2361	153	UAAGGAAUUCUGUCGGACUGA

2362	154	AUAUAGUUUGCUGAAACUCUA

2363	155	AUCUAGAACAGCUUGUGGGUU

2364	156	UACUUAAUGUCCAACAAGGAU

2365	157	UUCCUCUUCAUCUUCUUCUUC

2366	158	AACAUCUAGAACAGCUUGUGG

2367	159	UCAUAUAAGGAAUUCUGUCGG

2368	160	UUAGGUCCAAGUUUCAAACUG

2369	161	UUUCUCCUUCUUCUUAUUGGU

2370	162	UUCCUGUACAAAGUACUGGAA

2371	163	AUUAGUAGCUACAGGAUUCUG

2372	164	UAAUGAAUAUGGUAUUUGCGG

2373	165	UUGAGAACAUCUAGAACAGCU

2374	166	AUCUUCUUCUUCUUCUUCCUC

2375	167	UAUUCUACAUUUAUCUGGUUU

2376	168	UGAAACUAAGCAGCAUAUCUG

2377	169	UUCAUAGGAGAAAUAUUCCAU

2378	170	AAGACAUUUAUGAAUAUGCUU

2379	171	UCUAGUGCUGUAUAAACAGUA

2380	172	UAGCCUUCACUGACCUCCCAU

2381	173	UAUUUAACUGCAACAUAAGAG

2382	174	UUUCUAUUCAUUUGAAAGGUA

2383	175	UAGCUUCUCUAAGAUCUCCUC

2384	176	UUAUUAUGAACUUCAUUUGCU

2385	177	UUUACAAAUGCUGAAUUUCAG

2386	178	UUAUAAGAAGUUUCUAUUCAU

2387	179	UCAGUAUUCUACAUUUAUCUG

2388	180	UUUAUGGUCACUUCAACAUUG

2389	181	AUUGUUAAUAUGCUGAACUGA

2390	182	UUGCAGUCUUAGCGGCUGCUG

2391	183	AUACAGCUGACAGUCUCUCAG

2392	184	UAAAUACUUGAGUUAAAUCUU

2393	185	UAGUAGCUACAGGAUUCUGUG

2394	186	CUUGCUAACAACAUUAACGUU

2395	187	AUGGUCACUUCAACAUUGCUG

2396	188	UUCGUUUACUUUGCUCAGGAG

2397	189	UCACAUAAUUCCACCACCCUA

2398	190	AUAUACAGUAAUAUCCUGUUG

2399	191	UAUCACCUUUCUCUAGAUCUU

2400	192	UAUGAACUUCAUUUGCUUGAG

2401	193	UUAGAAAUAUACAUAACUCUC

2402	194	UAUUAUAACAAUAUCAAAUAA

2403	195	UAACUUCUAUUGAAAUUAGUG

2404	196	UUCUUCUUCCUCUUCAUCUUC

2405	197	UUGUCAACAUUUCUCAAUGCU

2406	198	UUCUGCUGUUUAUUUAUUGUA

2407	199	UAGAUGGUCUCCCUUGCUCUU

2408	200	AUACUCGUACACACAGGUGUG

2409	201	UUCUUCUUCUUCUUCCUCUUC

2410	202	AUACUUGAGUUAAAUCUUCUU

2411	203	UUGUAACUAGCAAAUAUCUCU

2412	204	UUCACAUAAUUCCACCACCCU

2413	205	UAAAGCUCAUGUAUUUCUGGU

2414	206	UAACUAGCAAAUAUCUCUGCC

2415	207	UAUUGAUUGGGAUGUAGCCUU

2416	208	AUAAUCUCUACUGUGCUUCUC

2417	209	UAAUCGUGCCCAUUGCUCUGG

2418	210	UUAGUAGCUACAGGAUUCUGU

2419	211	AAGGAGAUUAACAACCUGGUU

2420	212	UAAAGAAUAAAUACUUGAGUU

2421	213	UUUAACUGCAACAUAAGAGAC

2422	214	UCUAGGUAUAGGGUCUGCUUU

2423	215	AUGAACACACCAUAUUCCGAA

2424	216	UUGGAGUUCUAAUAGUGACAU

2425	217	AUAGUGACAUCUCCCUAGCUU

2426	218	UCACACAGUACUUGCUCUGGU

2427	219	UUUAGGUAUCAUUAUCUUUGU

2428	220	UAUUUCUGUAUUGAGAAUGAC

2429	221	UCUAAUGACAAUGCAAGUGAA

2430	222	UUCACACAGUACUUGCUCUGG

2431	223	UUCUUCUUCAGACACAGGAGG

2432	224	UCUGUCGGACUGACAUUUCUU

2433	225	UUCUUAUUCUUCUCUUCAGGG

2434	226	AAGGCUUAGAGAAACAACUUU

2435	227	UAAUAUGCUGAACUGAAAGCA

2436	228	UUAAUUGCUUCCUUUGCAGCG

2437	229	UUGUUCAGAGCUCAGAGACUG

2438	230	ACAUCUAGAACAGCUUGUGGG

2439	231	AUCUGUUGAACAUGUUGCCAG

2440	232	AAAUAAAUAAUCUCUACUGUG

2441	233	UUACAACUAAUUUCACAGCUC

2442	234	AUAGAAUACUCGUACACACAG

2443	235	UUACACGAUCUUUGAGCUGAG

2444	236	UAUGGUCACUUCAACAUUGCU

2445	237	UAUUCUAGCAAGUGUGACAGU

2446	238	UAAUAGUCUCCUAAGAAAGCG

2447	239	AACUAAGCAUGAACACACCAU

2448	240	UUUCAUAAGCACAAGAGAGGA

2449	241	UACUUUAGGUCCAAGUUUCAA

2450	242	UAUUAUCAAAUCUUGGUACAA

2451	243	UUUCGCUUCACGGUGGAAGUG

2452	244	UUAUACAGACAACAGGAAGCA

2453	245	UCGGACUGACAUUUCUUGGGA

2454	246	UCUUCUUCUUCAGACACAGGA

2455	247	UAUAUGGUGAAAUAGUAGUCA

2456	248	UUUCUCAAUGCUAAUAGCAUG

2457	249	UUUGUCCAUAUGCAUUUCUUU

2458	250	UUGCUAACAACAUUAACGUUC

2459	251	UCUAUAGUUCCCUUUCUGCUG

2460	252	UAGGUUCAGAACCUGAACUCA

2461	253	UCAUCUUACAUAGUUCUUUUA

2462	254	UUUAUAGACAAAUAUCUCAAA

2463	255	AAACUAAGCAGCAUAUCUGAG

2464	256	ACUCUUAGCAGUCUCAGCCAU

2465	257	AAAGCUUGCAGGCACUCUCUG

2466	258	UUAUGUUGGAAGUUUGGAGUA

2467	259	AUACUUAUUAGAAAUAUACAU

2468	260	UCUUUGGUGAGUUAGAAGGAA

2469	261	UAGAUAAUAGUCUCCUAAGAA

2470	262	AUCACCUUUCUCUAGAUCUUU

2471	263	UGAAGGAAGAGAGAUCUCUGG

2472	264	UCAUCCAUACAGGUCUCUGUG

2473	265	UACCAAAUGUGAAUCCUUCAG

2474	266	AUUCUGUGAAGAUCUUAUCAU

2475	267	UUCUUAAUUGCUUCCUUUGCA

2476	268	UAAGGAGAUUAACAACCUGGU

2477	269	UGAAUGUACAUAAGUUCUGUU

2478	270	UUUACUAUAUCACCUUUCUCU

2479	271	AUAAUUAUUUACACGAUCUUU

2480	272	UCAUCUGUCAUCUUGGAUUUU

2481	273	AUCAUCUAGUCCAAUACACUU

2482	274	AUAGUCUCCUAAGAAAGCGUG

2483	275	AUCUCCUGAACAUAAACACGU

2484	276	UAAGGGAUGCUAACUAAUGAA

2485	277	ACAACAGGAAGCAAUUUCGUG

2486	278	UGAAAUAGUAGUCAAAUUUUG

2487	279	UAUGUAACUGAUCUCUUUCCC

2488	280	AUUAACAAUAUUAGGGUUCUU

2489	281	UUUACUUUGCUCAGGAGUGAU

2490	282	UUGGUCACUUAAAGGAGUGUG

2491	283	UAUACAGUAAUAUCCUGUUGG

2492	284	UACAGUAAUAUCCUGUUGGAC

2493	285	AAGCACACCACACACAAGCAC

2494	286	AUUAUGAACUUCAUUUGCUUG

2495	287	UAAUUAAUUCCUUCUUGGGUU

2496	288	UAAAUAAUUAACAAUAUUAGG

2497	289	UUCUACAUUUAUCUGGUUUUG

2498	290	UUGCAAUGUCUAGUGCUGUAU

2499	291	UGUGCAUCUUUGAGAAACCUU

2500	292	UACAGCUGACAGUCUCUCAGG

2501	293	UGUAACUGAUCUCUUUCCCCU

2502	294	UCAAGUACAGUUAUAUUCUAG

2503	295	UGGACAUCUAAUGACAAUGCA

2504	296	ACUCAUUCUCUACUAUCGCUG

2505	297	UUGAGAAUUAAACUCUAGAAA

2506	298	UGAAUAGGGCUUCCUAACCAG

2507	299	AUUCUAGCAAGUGUGACAGUG

2508	300	UAAUGAUUUCAAAGUCAGCUU

2509	301	UAGCAAUUUAGUAAUAAAGCU

2510	302	UGACAGUCUCUCAGGAUUCUG

2511	303	AUCGCUGUUGAUUUCCUCUUG

2512	304	UGUUCCUGUACAAAGUACUGG

2513	305	UACAAUUCUGAUAAACAAUGA

2514	306	AUAAUUAAUUCCUUCUUGGGU

2515	307	AUUAAUAAUUAAUUCCUUCUU

2516	308	UUCUUCUUCUGUUCCAAUUUU

2517	309	AAGCAGAGGGCAGACAACCUG

2518	310	UUCUCUUCAUUAUCCAGACCG

2519	311	UUCUUUGGUGAGUUAGAAGGA

2520	312	UACAUCUGACUCAUUCUCUAC

2521	313	AAACACAACACUAUGAAGAGG

2522	314	UCUUAAUUGCUUCCUUUGCAG

2523	315	AUUUGAGAACAUCUAGAACAG

2524	316	UCGAACUCCUGACCUCAGGUG

2525	317	UAUGCUCAAAGUCUGAAGGAA

2526	318	UAGUUCAUCACCCACCAAGUA

2527	319	AUUUAUAGACAAAUAUCUCAA

2528	320	UAGAAAUAUACAUAACUCUCC

2529	321	UAGAUGUAAGGAUCAGGUGGU

2530	322	AAUUUAGGUAUCAUUAUCUUU

2531	323	AUAUAUUAUUAUCAAAUCUUG

2532	324	UCUGCAGACAGCUGCUAUCUG

2533	325	UAUCUUUGUUUACUUAAUGUC

2534	326	UAUUCCGAAACAGAAAUAGGU

2535	327	UAUCAUUAUCUUUGUUUACUU

2536	328	UGAACAUAAACACGUACACUA

2537	329	UUGAUUUCCUCUUGGGUACUA

2538	330	UAAACAGUACCUGAUGCCCCU

2539	331	UAGAAGGAAGUUAUCCUUUGG

2540	332	AAUAAUUAACAAUAUUAGGGU

2541	333	UCUUUGUUUACUUAAUGUCCA

2542	334	UGAACUGAAAGCAUAAGAGAG

2543	335	UAGAUAUAUGGUGAAAUAGUA

2544	336	UAGACAUCACUACCCUGUGAU

2545	337	AUAAAUAAUCUCUACUGUGCU

2546	338	UGCUAUCUGUCCUUCAUCCAU

2547	339	UUAGACAUUGUUUAAUAUUAA

2548	340	UUAUGAACUUCAUUUGCUUGA

2549	341	UUUCAUUAAUAAUUAAUUCCU

2550	342	UAACACAACUGAUUUCAAUUA

2551	343	AUUAGAAAUAUACAUAACUCU

2552	344	UUCAUCUUCUUCUUCAGACAC

2553	345	UUAAUGUCCAACAAGGAUUUC

2554	346	UCUUGGUACAAAGUGGUAGUA

2555	347	UACAGUGAUCUGAAGGGUCAC

2556	348	AUGACAACGCACUGGAUCCUU

2557	349	UUUAACUUAUAGAUAAUAGUC

2558	350	UUGGUACUGCUGGUGAAGCAA

2559	351	UGUUUAUUUAUUGUAAAGCAA

2560	352	UUGCAAGUCAUAACUUCUAUU

2561	353	AACACGUACACUAUAUAGUUU

2562	354	UUCAUAAGCACAAGAGAGGAU

2563	355	AACAACUGUAAAUGAAUUGGA

2564	356	UUCCCAUUUAUUUCCUUCCCA

2565	357	UUGGUGAGUUAGAAGGAAGUU

2566	358	UUUAUUGUAAAGCAAUAUUAU

2567	359	UAAGUAUUUCUGUAUUGAGAA

2568	360	UCUGGUUGUUGACUGUUUCUU

2569	361	AAUUGCAAGUCAUAACUUCUA

2570	362	AGACUUUACAUACAGACUGUA

2571	363	UAACACAAAUUGUUAGUUUUU

2572	364	UGGUUAAACUCAAACAUUGGG

2573	365	UUUCUCUCUGCAACUUGUAAG

2574	366	UAAUAAUUAAUUCCUUCUUGG

2575	367	UACUCGUACACACAGGUGUGC

2576	368	UGAUAUACAGUAAUAUCCUGU

2577	369	UCCUCGCCUAUCCACAUCCAU

2578	370	AUUUGCAAUACUUUAGGUCCA

2579	371	AUAAUCAGAGGAGUCAGGCUG

2580	372	UGUAUCUAUUUCCUCCUGGUA

2581	373	UAUAUGGAUGGUUAGAUGGAU

2582	374	UACUAUUCAUCCUCAGUGGAG

2583	375	AUAAGGAAUUCUGUCGGACUG

2584	376	AGAACUAUAACUGAAUGCCAA

2585	377	ACAAGCACACACAUUGAACUU

2586	378	UCACCUAGCAGGAUGUCACAG

2587	379	UUUGCAGCGAUAAUCAGAGGA

2588	380	UAACAGAACUAUAACUGAAUG

2589	381	UUGCUCAGGAGUGAUCUGGGC

2590	382	UUGGGAUGUAGCCUUCACUGA

2591	383	AUAUUGAUUGGGAUGUAGCCU

2592	384	UUAUUUAGAUAUACAGUUUUU

2593	385	UGUUGCAAUGUCUAGUGCUGU

2594	386	AACAGCUUCUUUCUAAUACUU

2595	387	UAGGUAUCAUUAUCUUUGUUU

2596	388	AUUGUAACUAGCAAAUAUCUC

2597	389	UUAGAAGGAAGUUAUCCUUUG

2598	390	AUUUCUUGGGAUAUGAUUGUA

2599	391	UUGAAGGUUCAUCUGCUUUAU

2600	392	UUAUCCUUUGGUUAGAUGGUC

2601	393	UCUUUAUUUGGUACUGCUGGU

2602	394	UCAUCAAUAAUGAAUAUGGUA

2603	395	UUUCAGUCUUACUCAUGAGGG

2604	396	UUAGAAGCUGUUCUCAUUUGA

2605	397	UCUUCUUCUUCUUCUUCCUCU

2606	398	UUAACAGAACUAUAACUGAAU

2607	399	UAAUAGCAUGUAAUUACUUUU

2608	400	AUAGACAAAUAUCUCAAACUA

2609	401	ACUCUCUGCAGACAGCUGCUA

2610	402	UUAUAUUCAUUUGGUCACUUA

2611	403	UCAGUCAAUUUAACAGAGCCA

2612	404	UUACAUAAUCUGAGGGAGUAG

2613	405	UUUAGAAGCUGUUCUCAUUUG

2614	406	ACUUCUAUUGAAAUUAGUGGG

2615	407	UUAACUGCAACAUAAGAGACU

2616	408	UUUGUAUCAUAAGUAAAUGAU

2617	409	UCUUCUUCAGACACAGGAGGG

2618	410	UUCACUGACCUCCCAUUUCUU

2619	411	UCCUCUUGGGUACUAAAUCUG

2620	412	AUCUCCUCAUCUGUCAUCUUG

2621	413	AAUAAUUAAUUCCUUCUUGGG

2622	414	AUUGUCACUCUUUAUAUCUCU

2623	415	UGUCGGACUGACAUUUCUUGG

2624	416	UGAAUUUGCAAGGCAACCUAU

2625	417	UUUACAUGAAUACAAAUUUAU

2626	418	UAUUAGGGCAUGGACUUCCAC

2627	419	UUUCCCGGCACUAUGAGUGAA

2628	420	UACAUAACUCUCCAAUACAGG

2629	421	ACAAAUAUCUCAAACUAUCAA

2630	422	UAGGUACACAAACCAAGCCAC

2631	423	UUCUGUCGGACUGACAUUUCU

2632	424	UUCAACAUUGCUGCCCUGUUU

2633	425	UGAAGAGGGAGUGUGCAUCUU

2634	426	UGAAACUCUAAAGAAAGUGCU

2635	427	UGUCACUCUUUAUAUCUCUAU

2636	428	UUCAUUUGGUCACUUAAAGGA

2637	429	AAGCUCAUAUUAGACUCCGGG

2638	430	AUACAUAACUCUCCAAUACAG

2639	431	UGUCUAGUGCUGUAUAAACAG

2640	432	UAGUGACAUCUCCCUAGCUUU

2641	433	UUCUAUUGAAAUUAGUGGGAC

2642	434	UUAUUUAUUGUAAAGCAAUAU

2643	435	AUAUGGUGAAAUAGUAGUCAA

2644	436	UGAAGCAAUGGAUUCAACCAC

2645	437	UUGUCCAUAUGCAUUUCUUUU

2646	438	UUCCGAAACAGAAAUAGGUGA

2647	439	AUUAGAAAUAAACCCAUUGAG

2648	440	UAAUUCCUUCUUGGGUUGCUG

2649	441	UGGGAUUAUGACAACGCACUG

2650	442	UUCAUUAUCCAGACCGUCAGA

2651	443	UCUCUUCAUUAUCCAGACCGU

2652	444	UUCUUUGGAAUCAUAGAAUUU

2653	445	AUAUUCUAGCAAGUGUGACAG

2654	446	UACUGCAAAUUAAGAAGCCUU

2655	447	AAAUAAAUUACAUAAUCUGAG

2656	448	AAAGUAUAACAUAGUAUGCUU

2657	449	UGACUCAUUCUCUACUAUCGC

2658	450	AGUACAGUUAUAUUCUAGCAA

2659	451	AACAUUAACGUUCUUUCCUUU

2660	452	UUAUCAUCAAUAAUGAAUAUG

2661	453	UUUAUUUCCUUCCCAGUCCAC

2662	454	UAGCGUCACAUAGCAAUUUAG

2663	455	UACAGGUCUCUGUGACCACAU

2664	456	UUUCCCACUGCCCUAUUCCUA

2665	457	UAUGUAUCCAUGUGCACUUUU

2666	458	UCAGUCUUACUCAUGAGGGAG

2667	459	AUAGGAAAUACACCAGUGGGG

2668	460	AAACAACCUAUAAAUAGGCAG

2669	461	AUCAUUAUCUUUGUUUACUUA

2670	462	UAUAGAAUACUCGUACACACA

2671	463	AAUAGUGACAUCUCCCUAGCU

2672	464	AUCUCUAUGGAUCACCUGGUU

2673	465	UUAACAAUAUUAGGGUUCUUA

2674	466	UCUCUAAGAUCUCCUCAUCUG

2675	467	UCCUCAUCUGUCAUCUUGGAU

2676	468	UUCAUCCAUACAGGUCUCUGU

2677	469	UGAAUGUUUACUAUAUCACCU

2678	470	ACAGAUAACACAUUCUGACAA

2679	471	UUUACACGAUCUUUGAGCUGA

2680	472	AAUACUCGUACACACAGGUGU

2681	473	AAAUCUUGGUACAAAGUGGUA

2682	474	AUAUCUGAGGUGACUACCUCA

2683	475	UCUCUCAUUAGAGCAGUGUGG

2684	476	UUGGAAGUUUGGAGUAAUCGU

2685	477	UUGGUUAGAUGGUCUCCCUUG

2686	478	UUUGAGCUGAGAAAUAUCAUU

2687	479	UUGAUUGGGAUGUAGCCUUCA

2688	480	UGACCUCAGGUGAUCCGCCUG

2689	481	AAUAUUUACAAUGACACACAC

2690	482	UGGAUUCAACCACAGAACGAG

2691	483	UUUCUGUAUUGAGAAUGACCA

2692	484	UUGUUAAUAUGCUGAACUGAA

2693	485	ACAACUGAUUUCAAUUAUCUG

2694	486	UGCUUAACUGAAUAUUAACUG

2695	487	AUUGCAAGUCAUAACUUCUAU

2696	488	AAUGUUUACUAUAUCACCUUU

2697	489	UGCUUCGUUUACUUUGCUCAG

2698	490	AAAGCUCAUAUUAGACUCCGG

2699	491	UGUCAGUUUACAAAUGCUGAA

2700	492	UGAACUUCAUUUGCUUGAGUU

2701	493	UCCACCACCCUAACACAACUG

2702	494	UAUGGUGAAAUAGUAGUCAAA

2703	495	AAUGAUUUCAAAGUCAGCUUU

2704	496	UCACUCUUGUUGCCGAGGCUG

2705	497	AAGAACGAAGUCAUUACCCAA

2706	498	UUUAAAUGUGGUUUCUCCUAU

2707	499	AACAUAAAGAAUAAAUACUUG

2708	500	AUGCAUUAGUAGCUACAGGAU

2709	501	UCGCCUAUCCACAUCCAUCUC

2710	502	AAUGUAUCUAUUUCCUCCUGG

2711	503	UAUUGUCACUCUUUAUAUCUC

2712	504	UAUUCAUCCUCAGUGGAGGAG

2713	505	UGAGUGCUGAAGAAUCCCGGU

2714	506	UGACUUCUCUAGGUAUAGGGU

2715	507	UCAUUUGGUCACUUAAAGGAG

2716	508	UUAUCUUUGUUUACUUAAUGU

2717	509	AUAUUAUUAUCAAAUCUUGGU

2718	510	UAAGCAUGAACACACCAUAUU

2719	511	AUGAAUAUGGUAUUUGCGGGU

2720	512	UUAUUGUAAAGCAAUAUUAUA

2721	513	UGUUUCUUUGGAAUCAUAGAA

2722	514	UACUCUCAGAAGAUUCAGGAA

2723	515	UCCUGAACACACAUAUUCCUC

2724	516	AUGGAUUCAACCACAGAACGA

2725	517	UGCAAGAGGGACUACUCUCUA

2726	518	UUCCUAACUCAGGACAUUUUG

2727	519	UAUAACAUAGUAUGCUUCAAA

2728	520	AAUUUCAGUCCUCUUGUUCAG

2729	521	UUAGUAAUAAAGCUCAUAUUA

2730	522	UCACUCUUUAUAUCUCUAUGG

2731	523	UUUCUCUAUGUUGGUCAGGCU

2732	524	UAUUAAGGAGAUUAACAACCU

2733	525	UCGCUGUUGAUUUCCUCUUGG

2734	526	UAUGUUGGAAGUUUGGAGUAA

2735	527	UACCUGAAUGAUAUACAGUAA

2736	528	UACACUCAAGACACAGUCAUG

2737	529	UCUCUGCCUACAGUGAUCUGA

2738	530	UUGGGUUAUAUUCAUUUGGUC

2739	531	UAGGUAUAGGGUCUGCUUUUA

2740	532	UUCAAAUUAAUAUUACCGUUU

2741	533	UAUAUAGUUUGCUGAAACUCU

2742	534	UAGUCUCCUAAGAAAGCGUGU

2743	535	AAUCGUAUGCUCAAAGUCUGA

2744	536	AUCAGAAAUGCUAUCUUUGGU

2745	537	UAGAAGCUGUUCUCAUUUGAA

2746	538	UUUAGUAAUAAAGCUCAUAUU

2747	539	AAACACGUACACUAUAUAGUU

2748	540	AAUGCUUCUUAGCUUCUCUAA

2749	541	UAUUGAAAUUAGUGGGACUUG

2750	542	AUUUGGAUAGACUCACCUGUG

2751	543	UAUCUAAAUAAUUAACAAUAU

2752	544	UUUCCUAGGUUCAGAACCUGA

2753	545	AUAAUGAAUAUGGUAUUUGCG

2754	546	UAAGAAGUUUCUAUUCAUUUG

2755	547	UAAAGCAAUAUUAUAACAAUA

2756	548	AACAGGAAGCAAUUUCGUGUU

2757	549	UUCACUCUUGUUGCCGAGGCU

2758	550	UUAAUGAUUUCAAAGUCAGCU

2759	551	UAAGCAGCAUAUCUGAGGUGA

2760	552	UAUGGGAUAGCAUUUGCCUGA

2761	553	UCUCAGAGAAAGUCCCAUCUU

2762	554	UUGCAGAUUCAGUUAGACAUU

2763	555	UAGCAAUGGAAUGUGCUUCAC

2764	556	UCCAUUAUUUCCAAGUUCCCA

2765	557	UUCACAGGAAAGGAGAAGCUC

2766	558	UGACUGUUUCUUUGGAAUCAU

2767	559	UAUGUUUCAUAAGCACAAGAG

2768	560	AGUAGCUUAGAUAAAGACCAA

2769	561	UGUGCUUCUCACCCUUCCCUG

2770	562	UUUAUCUUGCAAGUUCAACCC

2771	563	AAAUAAUUAACAAUAUUAGGG

2772	564	UCCACAUCCAUCUCAAGACAG

2773	565	ACACAGUCAUGCACAAUCCAU

2774	566	AUUAAUUUGUCAACAUUUCUC

2775	567	UCUGAAGGGUCACUGCUCCAA

2776	568	AACAGCUUGUGGGUUCUUCUU

2777	569	UAGGAAAUACACCAGUGGGGU

2778	570	AUAUUAUAGAAUCUCUCAGAA

2779	571	UGAGAAACAGCUUCUUUCUAA

2780	572	UGGGAUUACAGGUAUGAGCCA

2781	573	UUAGGUUCACUCUUAGCAGUC

2782	574	UGCUGUAUAAACAGUACCUGA

2783	575	UAGAUGGAUGGAUGUACCUUG

2784	576	UCUUCUUCUGUUCCAAUUUUG

2785	577	UGGUCUCGAACUCCUGACCUC

2786	578	UAAUCCAAAGUUACAGAAGAA

2787	579	AUAUUAACUGCAAGUAGCUUA

2788	580	AAGGAUUUCAGUAUUCUACAU

2789	581	UUGAGCUGAGAAAUAUCAUUU

2790	582	UGGAGCUGUGGUUGAGUGCUG

2791	583	UUCCUAACCAGGUAUUGGGCU

2792	584	AUCAUCAAUAAUGAAUAUGGU

2793	585	AGAACAUCUAGAACAGCUUGU

2794	586	UACCUCAUUAUUAAAGUUCUC

2795	587	UCAUUUAUAGACAAAUAUCUC

2796	588	AAUAAACUGUUAACAAUCUGG

2797	589	UACUGCUGGUGAAGCAAUGGA

2798	590	UCUCCUAUGAGGAUUUCCUAG

2799	591	UAACUCUCCAAUACAGGGAAG

2800	592	ACAAUUCUGAUAAACAAUGAA

2801	593	UAUUAGAAAUAUACAUAACUC

2802	594	AUAGAUGUAAGGAUCAGGUGG

2803	595	UGUAUUUCUGGUUGUUGACUG

2804	596	AUGGUGACUGAUUUGAGGGGA

2805	597	AAUGAAUAUGGUAUUUGCGGG

2806	598	ACUCUUUAUAUCUCUAUGGAU

2807	599	UUCCAGCAGUGUACUCAUCAU

2808	600	UUGUAUCAUAAGUAAAUGAUG

2809	601	UAAUCUCUACUGUGCUUCUCA

2810	602	AUGUUCACACAGUACUUGCUC

2811	603	UUUGAGUGCAGGAAAUCCAAA

2812	604	AAUGGAAUGUGCUUCACCGGG

2813	605	UCUCUCAGGAUUCUGGAGCUC

2814	606	AAACUCUAAAGAAAGUGCUUU

2815	607	UCUUGGGUACUAAAUCUGUUG

2816	608	AAUUAAACUCUAGAAAGCCCA

2817	609	AUAUUUACAAUGACACACACA

2818	610	UUCUUCCUCUUCAUCUUCUUC

2819	611	UAUCUCCUGAUGUAAAGCUCA

2820	612	UUUGCUGAAACUCUAAAGAAA

2821	613	UUGGUGCGAUAACUGGUGGUG

2822	614	UAAUUAUUUACACGAUCUUUG

2823	615	UAUUUCCUCCUGGUAUGCCUA

2824	616	ACAAAUAAAUUACAUAAUCUG

2825	617	AUUUACAUGAAUACAAAUUUA

2826	618	UACACAGACACUCCGCAGAUA

2827	619	UGGGUUCUUCUUCUGUUCCAA

2828	620	UGGAUCCUUGCUAACAACAUU

2829	621	UCUCUGCAACUUGUAAGUGUU

2830	622	UACAUGAAUACAAAUUUAUAA

2831	623	UCAAGUUACUCGAUUGUACCA

2832	624	UCUGUGACCACAUCAGUCAGA

2833	625	AUAACUCUCCAAUACAGGGAA

2834	626	UUCACUACACAUGGUUUACAG

2835	627	UAACUGCAACAUAAGAGACUC

2836	628	AACUGAUUUCAAUUAUCUGUG

2837	629	UGCUGUUCUUAAUUGCUUCCU

2838	630	UCUCAAUGCUAAUAGCAUGUA

2839	631	AUUUACAAUGACACACACACG

2840	632	AUACAGUAAUAUCCUGUUGGA

2841	633	AUGAGGAUUUCCUAGGUUCAG

2842	634	AACUUCUAUUGAAAUUAGUGG

2843	635	UGCAUCUUUGAGAAACCUUUU

2844	636	UCAGAAAUGCUAUCUUUGGUU

2845	637	AUCUGCAACAGAUGUUAUCAA

2846	638	AUUGCAACUCUAUUAGGGCAU

2847	639	UGUAAAGCUCAUGUAUUUCUG

2848	640	AGAUUUGGAUAGACUCACCUG

2849	641	UUCCACCAUUUCAAUUGCCAU

2850	642	UUACUCGAUUGUACCAAAUGU

2851	643	UUUGCUCAGGAGUGAUCUGGG

2852	644	UAACAUAGUAUGCUUCAAAUU

2853	645	UCAAAUCUUGGUACAAAGUGG

2854	646	AAUCUUGGUACAAAGUGGUAG

2855	647	UUCCUUCUUGGGUUGCUGUUG

2856	648	GAGAACAUCUAGAACAGCUUG

2857	649	AUUAUUAAAGUUCUCACCUAA

2858	650	AAGGCUUGCAGUCUUAGCGGC

2859	651	UGCAUUAGUAGCUACAGGAUU

2860	652	AGAAUUUCACUACACAUGGUU

2861	653	UUGUAAUCCCUGUUUAUGUUA

2862	654	UGGUUGUUGACUGUUUCUUUG

2863	655	UUAGAUGGUCUCCCUUGCUCU

2864	656	UCUGGAGCUCUGGAGUUCCAU

2865	657	ACUCACAAUGCUUCUUAGCUU

2866	658	AUAACUUCUAUUGAAAUUAGU

2867	659	UCAACAUUGAAAGAUGUGCCC

2868	660	UCAUCACCCACCAAGUAGCUA

2869	661	AAGUCAGUCAAUUUAACAGAG

2870	662	UAGGGCAUGGACUUCCACAUG

2871	663	AUCUCAGCUCACCACAACCUC

2872	664	AUGUUAUGAGUAUAAUCCCAG

2873	665	UUUCAUUGAAUUUCCCGGCAC

2874	666	UAUUCCAUUAUUUCCAAGUUC

2875	667	AAGAAUAUUGUCACUCUUUAU

2876	668	AGAAAUAUACAUAACUCUCCA

2877	669	UUACAGAAGAAUUUCACUACA

2878	670	UAUAAUCCCAGUAGACAUCAC

2879	671	UUUGUCAACAUUUCUCAAUGC

2880	672	UGGUCUUGGUGCGAUAACUGG

2881	673	AAGUAAAUGAUGAUUAAUGUA

2882	674	UACUUAUUAGAAAUAUACAUA

2883	675	AUAUCUCUAUGGAUCACCUGG

2884	676	UUGACUGUUUCUUUGGAAUCA

2885	677	UCUGUAUUGAGAAUGACCAAU

2886	678	UUCAACCUGAGAGUCUGUUAA

2887	679	UUGUUUAAUGAUUUCAAAGUC

2888	680	AUUCCGAAACAGAAAUAGGUG

2889	681	ACUAAAUCUGUUGAACAUGUU

2890	682	UAAUCAGAGGAGUCAGGCUGG

2891	683	AAGUAUAACAUAGUAUGCUUC

2892	684	UACACGAUCUUUGAGCUGAGA

2893	685	AAAUGCUGAAUUUCAGUCCUC

2894	686	CUAAGCAGCAUAUCUGAGGUG

2895	687	UUCUAUUCAUUUGAAAGGUAA

2896	688	UUUGCAGAUUCAGUUAGACAU

2897	689	UAGCUUUAACUUAUAGAUAAU

2898	690	UAAUCCCAGUAGACAUCACUA

2899	691	UAUAUUCAUUUGGUCACUUAA

2900	692	UAGUAAUAAAGCUCAUAUUAG

2901	693	UUCUCUAGGUAUAGGGUCUGC

2902	694	UCAAUGCAUUAGUAGCUACAG

2903	695	GUGCUGUAUAAACAGUACCUG

2904	696	AAUAUGCUGAACUGAAAGCAU

2905	697	UAAUAAAUAGAUAUAUGGUGA

2906	698	AUUAAACUCUAGAAAGCCCAG

2907	699	AUCUGACUCAUUCUCUACUAU

2908	700	AGACAGCUGCUAUCUGUCCUU

2909	701	AAUUCUGUCGGACUGACAUUU

2910	702	UAUUUGUUUAAUGAUUUCAAA

2911	703	UGUCAACAUUUCUCAAUGCUA

2912	704	UAGUUUGCUGAAACUCUAAAG

2913	705	UGUUUCAUAAGCACAAGAGAG

2914	706	AUGUGACAGGAUUUCACCGUU

2915	707	AUACUGCAAAUUAAGAAGCCU

2916	708	UAAUUGCAAGUCAUAACUUCU

2917	709	UUAUCCAGACCGUCAGACAUU

2918	710	UUUAUUUGGUACUGCUGGUGA

2919	711	AAUUGCUUCCUUUGCAGCGAU

2920	712	UAAGUGACUUGCCUAGCGUCA

2921	713	AUCAAAUCUUGGUACAAAGUG

2922	714	UCAUGGGAUUAUGACAACGCA

2923	715	UACAGUUAUAUUCUAGCAAGU

2924	716	ACAAGUUGUAUAGAAUACUCG

2925	717	AGAAUUUGAGAACAUCUAGAA

2926	718	UUCAGUUAGACAUUGUUUAAU

2927	719	UAAAUGAUGAUUAAUGUAUCU

2928	720	AAUGAUAUACAGUAAUAUCCU

2929	721	AAGUCAUUACCCAACAUGGUG

2930	722	UCUUCUUCUUCUUCCUCUUCA

2931	723	UAUUAACUGCAAGUAGCUUAG

2932	724	UGGUAGUAAAGAAGUACCUGG

2933	725	UAAGUUCUGUUUAGAUUCUUU

2934	726	UAUAAGAAGUUUCUAUUCAUU

2935	727	ACAACAUUAACGUUCUUUCCU

2936	728	UUCAAGACAUUUAUGAAUAUG

2937	729	ACAACUGUAAAUGAAUUGGAA

2938	730	AUUGUUUAAUAUUAAACACAU

2939	731	UAAAUCUGUUGAACAUGUUGC

2940	732	AACAUUGCUGCCCUGUUUGGG

2941	733	UUUCUUUGGAAUCAUAGAAUU

2942	734	UGAGUUCACUUCAAAUCCCAG

2943	735	UAAACGUUAUAAAUUGUCAAA

2944	736	UAGGGCUUCCUAACCAGGUAU

2945	737	UGUAAAGCAAUAUUAUAACAA

2946	738	UUAAAUGUGGUUUCUCCUAUG

2947	739	UCUUGGUGCGAUAACUGGUGG

2948	740	UCAGAACCUGAACUCACCUAG

2949	741	UUUCUUGGGAUAUGAUUGUAA

2950	742	UUAAUAUUACCGUUUCAUUUU

2951	743	UGAGCUGAGAAAUAUCAUUUA

2952	744	UUGUGGGUUCUUCUUCUGUUC

2953	745	UUGAGCUUUAUUUAGAUAUAC

2954	746	AGACCAGAUAUCAACUUUCGG

2955	747	GAAAUAUACAUAACUCUCCAA

2956	748	AAGAUUUGGAUAGACUCACCU

2957	749	UCUACUAUCGCUGUUGAUUUC

2958	750	AUGGUUUACAGAUAACACAUU

2959	751	UAUCAUAAGUAAAUGAUGAUU

2960	752	AUAAAGCACACCACACACAAG

2961	753	UCAGCUCACCACAACCUCCGC

2962	754	AAUAGUCUCCUAAGAAAGCGU

2963	755	UACAGAGUUGAAUGUUUACUA

2964	756	UUCCUAGGUUCAGAACCUGAA

2965	757	UUUGGUCACUUAAAGGAGUGU

2966	758	AAAGGCUUAGAGAAACAACUU

2967	759	AAAUUAGUGGGACUUGCCCUA

2968	760	AAAUUACAUAAUCUGAGGGAG

2969	761	AUUGCUUCAACCACAAUUUAA

2970	762	UACAAGUUGUAUAGAAUACUC

2971	763	UAAUUAACAAUAUUAGGGUUC

2972	764	AACAUAAACACGUACACUAUA

2973	765	AACUUUCGGACCAUAAGCUUU

2974	766	UUAUGAGUAUAAUCCCAGUAG

2975	767	UCUCAGAAGAUUCAGGAAGUG

2976	768	UGAUUAAUGUAUCUAUUUCCU

2977	769	AAUCAUAGAAUUUGAGAACAU

2978	770	ACAGCUGACAGUCUCUCAGGA

2979	771	UCAUCCUCAGUGGAGGAGCCG

2980	772	ACUAGCAACAUCAAAGAUUUG

2981	773	UAGCAACAUCAAAGAUUUGGA

2982	774	CAGUAUUCUACAUUUAUCUGG

2983	775	AACACACAUAUUCCUCUCCAC

2984	776	UUAAACUCUAGAAAGCCCAGC

2985	777	AACACAACUGAUUUCAAUUAU

2986	778	UAGAAAUAAACCCAUUGAGCA

2987	779	UACAGAUAACACAUUCUGACA

2988	780	UUGGAGCUGUGGUUGAGUGCU

2989	781	AACGAGUAUAGAUUGAUUUUG

2990	782	UGAUCUGGGCACAGAACCCAA

2991	783	AUGGAGACCAUCCCAAGCCAA

2992	784	AGUUAGAAGGAAGUUAUCCUU

2993	785	CUUAUAGAUAAUAGUCUCCUA

2994	786	UACCUUUGCUUAACUGAAUAU

2995	787	UUCUCUAAGAUCUCCUCAUCU

2996	788	UCAAGACACAGUCAUGCACAA

2997	789	AUGACACACACACGAGAUCAG

2998	790	UGGAAUUCCAGUGAAUUCCCC

2999	791	UCUCUCUCUCAUUAGAGCAGU

3000	792	UGAAUCCUUCAGCAUCACUGU

3001	793	AUUAACUGCAAGUAGCUUAGA

3002	794	UUCCAAGAGACCAGAUAUCAA

3003	795	AUAAUUGUAACUAGCAAAUAU

3004	796	UUCAGAGCUCAGAGACUGGGA

3005	797	UUAUCCCACUACAUCUGACUC

3006	798	AAUAAAUAGAUAUAUGGUGAA

3007	799	UCUCAGUUCCCGCAUUUGCAG

3008	800	UUACAAAUGCUGAAUUUCAGU

3009	801	UGUAAAUGAAUUGGAAGGCUG

3010	802	UAGGUUCACUCUUAGCAGUCU

3011	803	UUACCCUCUUUCCAGCAGUGU

3012	804	UGUUGAAGGUUCAUCUGCUUU

3013	805	UUUCAGUCCUCUUGUUCAGAG

3014	806	UCUUUGGAAUCAUAGAAUUUG

3015	807	UAACUCCCAGUUUACCCUCUU

3016	808	UCUCCUUCUUCUUAUUGGUUU

3017	809	UAGGCUAGUAUUUAUCCCACU

3018	810	UUAUCUCAGGGCACACUAGCA

3019	811	AAAUACUUGAGUUAAAUCUUC

3020	812	AGUUAUAUUCUAGCAAGUGUG

3021	813	UAAACCCAUUGAGCAAAGGAA

3022	814	UACUAUCGCUGUUGAUUUCCU

3023	815	AAUACAGCUGACAGUCUCUCA

3024	816	UCUUUCUCCUUCUUCUUAUUG

3025	817	UCAACUUUCGGACCAUAAGCU

3026	818	UUGAGCAAAGGAAUAUAAUUA

3027	819	UUGAAAGAUGUGCCCUCGUUA

3028	820	AUUUCUCUCUGCAACUUGUAA

3029	821	UGAAAGAAAUCUGAAUAACAU

3030	822	UCUUUCUAAUACUUAUUAGAA

3031	823	AACUGCAACAUAAGAGACUCA

3032	824	UUAAUUUAGGUAUCAUUAUCU

3033	825	AGAAAUAUCAUUUAUAGACAA

3034	826	CAUAUAAGGAAUUCUGUCGGA

3035	827	AAGUGUUUAGGUUCACUCUUA

3036	828	UGAUCUGAAGGGUCACUGCUC

3037	829	UGACCUCUUUAUUUGGUACUG

3038	830	UACUCGAAGGAUGGGCUGCUA

3039	831	AUUAACAACCUGGUUUACUCA

3040	832	UGAGUUAAAUCUUCUUACAUG

3041	833	AUUCCUUCUUGGGUUGCUGUU

3042	834	AAUGCAUUAGUAGCUACAGGA

3043	835	ACUAGCAAAUAUCUCUGCCCU

3044	836	UGUGACAGGAUUUCACCGUUU

3045	837	AACACAUUCCCAAUGCAUGUU

3046	838	AAUAAUUUGUAUCAUAAGUAA

3047	839	AUUAUUAUGAACUUCAUUUGC

3048	840	UAUGCUGAACUGAAAGCAUAA

3049	841	AUAAACACGUACACUAUAUAG

3050	842	UUACUGCUGGUAUUAUGGGAU

3051	843	AUCUAGUCCAAUACACUUAUU

3052	844	UCUUAGCUUCUCUAAGAUCUC

3053	845	UGCUGAAUUUCAGUCCUCUUG

3054	846	ACUAUCGCUGUUGAUUUCCUC

3055	847	ACACAUAUUCCUCUCCACUUU

3056	848	UUCUUUCUAAUACUUAUUAGA

3057	849	UGGAAUGUGCUUCACCGGGGA

3058	850	UCAUUGAUGUUUGUCAUUUUU

3059	851	AAAUGAUGAUUAAUGUAUCUA

3060	852	AAUUUGUCAACAUUUCUCAAU

3061	853	UUCAGUAUUCUACAUUUAUCU

3062	854	UCUAGUCCAAUACACUUAUUU

3063	855	ACAACUUUCUGUAAUUUACAA

3064	856	UUCUGGUUGUUGACUGUUUCU

3065	857	UUCUGUGAAGAUCUUAUCAUC

3066	858	UUAAUUCCUUCUUGGGUUGCU

3067	859	AUCUCUGCCCUGCAUGCUCUG

3068	860	UGUGGUUUCUCCUAUGAGGAU

3069	861	AUGUAACUGAUCUCUUUCCCC

3070	862	UACAGAAGAAUUUCACUACAC

3071	863	UUAAGAAGCCUUCUAUAACAC

3072	864	AAAUGCUAUCUUUGGUUCCCA

3073	865	UAAGAAGCCUUCUAUAACACA

3074	866	UUUGGAGUAAUCGUGCCCAUU

3075	867	AUUAAGGCCUCUCUCUCUCAU

3076	868	AUUUGAAAGGUAAAGAACCCC

3077	869	UUUGUUUAAAUGUGGUUUCUC

3078	870	UAUCAGAUACAAUGCCCUGAG

3079	871	UUUGGUACUGCUGGUGAAGCA

3080	872	AACACAACACUAUGAAGAGGG

3081	873	UUUCAAGACAUUUAUGAAUAU

3082	874	UGGAUCCUUCUCAACUUGUUU

3083	875	UAUAAACAGUACCUGAUGCCC

3084	876	UAGCAGGAUGUCACAGUUUCA

3085	877	AAAUCUGUUGAACAUGUUGCC

3086	878	UUCAACCACAGAACGAGUAUA

3087	879	AUGUACAUAAGUUCUGUUUAG

3088	880	UCUGAAGGAAGAGAGAUCUCU

3089	881	UGUCAUCAGAAAUGCUAUCUU

3090	882	AUCGUAUGCUCAAAGUCUGAA

3091	883	UUCUUCUUCUUCCUCUUCAUC

3092	884	UCUCUCUCAUUAGAGCAGUGU

3093	885	CACACAAGCACACACAUUGAA

3094	886	AUGGGAAGUGGUUUGGAGCUG

3095	887	UAUAGAUAAUAGUCUCCUAAG

3096	888	GAAUAAACUGUUAACAAUCUG

3097	889	UGCAUGUUGGGUUAUAUUCAU

3098	890	UCUAAGAUCUCCUCAUCUGUC

3099	891	UGGAAGUGACCACUUUAUGGU

3100	892	UCUCUAGGUAUAGGGUCUGCU

3101	893	UCUGCAACUUGUAAGUGUUUA

3102	894	UAUUGUAAAGCAAUAUUAUAA

3103	895	AUAUGCUGAACUGAAAGCAUA

3104	896	AAAUCUGAAUAACAUAAAGAA

3105	897	UUCAUCACCCACCAAGUAGCU

3106	898	AGUAGCUACAGGAUUCUGUGA

3107	899	ACAGUUAUACAGACAACAGGA

3108	900	AGAGGUUAAGUGACUUGCCUA

3109	901	UAGACAUUGUUUAAUAUUAAA

3110	902	UGAACACACAUAUUCCUCUCC

3111	903	UUCACUUCAAAUCCCAGGCCC

3112	904	UAUUCCAUGACUACCCAUAGU

3113	905	UGGGAGAUACUUGCACUACUG

3114	906	AACAAGGAUUUCAGUAUUCUA

3115	907	ACAGGUGUGCACAUGGAGGUG

3116	908	UCCAAUCUAAAGCAACCACAA

3117	909	AAUUCCACCACCCUAACACAA

3118	910	UCUUGGGUUGCUGUUGAAGGU

3119	911	AAAGUCUGAAGGAAGAGAGAU

3120	912	UAUUUACAAUGACACACACAC

3121	913	GUAUUCUACAUUUAUCUGGUU

3122	914	UGUUACUAUUCAUCCUCAGUG

3123	915	AAUACCUUUAAUCCAAAGUUA

3124	916	UAAAGAAAGUGCUUUCAUUUU

3125	917	AGAUAUCAACUUUCGGACCAU

3126	918	AACAAAUUAAUUUGUCAACAU

3127	919	UGGUUUGGAGCUGUGGUUGAG

3128	920	ACACAUUGAACUUGAAUUUUG

3129	921	UCAAAGAUUUGGAUAGACUCA

3130	922	UGGAAUCAUAGAAUUUGAGAA

3131	923	AGCACACACAUUGAACUUGAA

3132	924	UUGCAGCGAUAAUCAGAGGAG

3133	925	AUAAUUUGUAUCAUAAGUAAA

3134	926	AGAGGGACUACUCUCUAACUU

3135	927	CUAGCAAAUAUCUCUGCCCUG

3136	928	AAUUUCACUACACAUGGUUUA

3137	929	UUCUAGCAAGUGUGACAGUGU

3138	930	UUUACUUAAUGUCCAACAAGG

3139	931	AAUCAGAGGAGUCAGGCUGGA

3140	932	AAGCACACACAUUGAACUUGA

3141	933	UUGGGAUAUGAUUGUAAGUUA

3142	934	UCACUUCAACAUUGCUGCCCU

3143	935	GAACAUCUAGAACAGCUUGUG

3144	936	UAGUGAAACUAAGCAGCAUAU

3145	937	AAGUACAGUUAUAUUCUAGCA

3146	938	UGAAUUUCCCGGCACUAUGAG

3147	939	AAGUUUGGAGUAAUCGUGCCC

3148	940	UAUGAGUAUAAUCCCAGUAGA

3149	941	AACAUGGACACACAAAUAUUU

3150	942	UUCUUCCUAGGCUAGUAUUUA

3151	943	AAGCCCUUCCUGAACACACAU

3152	944	ACAUUUAUGAAUAUGCUUUUG

3153	945	ACUGUCAGUUUACAAAUGCUG

3154	946	UAUUAUGGGAUAGCAUUUGCC

3155	947	AUUUAUUUCCUUCCCAGUCCA

3156	948	ACACACACACGAGAUCAGCAA

3157	949	UGUCCAACAAGGAUUUCAGUA

3158	950	UGUAUUGAGAAUGACCAAUAA

3159	951	UUUCUGGUUGUUGACUGUUUC

3160	952	ACACAGUCACUAAUGUACUGA

3161	953	UUCCCGCAUUUGCAGAUUCAG

3162	954	UUCUUACAGAGUUGAAUGUUU

3163	955	AAUGCUACAAGUUGUAUAGAA

3164	956	AAUCCUUCAGCAUCACUGUGG

3165	957	AGUUUCACUCUUGUUGCCGAG

3166	958	UCAUCUUCUUCUUCAGACACA

3167	959	UUGCAAUACUUUAGGUCCAAG

3168	960	UAUGUUGGUCAGGCUGGUCUC

3169	961	UUUACCCUCUUUCCAGCAGUG

3170	962	UCUACACAGACACUCCGCAGA

3171	963	ACAGCUUCUUUCUAAUACUUA

3172	964	CAACUUUCGGACCAUAAGCUU

3173	965	AAAGCCUAUGGAAUAAUUGUA

3174	966	AUGAUUUCAAAGUCAGCUUUU

3175	967	UUCCUUCCCAGUCCACAUGCA

3176	968	AUGUUGGUCAGGCUGGUCUCG

3177	969	UAUCUGUCCUUCAUCCAUACA

3178	970	UUGCAACUCUAUUAGGGCAUG

3179	971	AUGCUAACUAAUGAAUAGGGC

3180	972	UGUUCUUAAUUGCUUCCUUUG

3181	973	AUCUGAAGGGUCACUGCUCCA

3182	974	UACUAAAUCUGUUGAACAUGU

3183	975	ACUUAUAGAUAAUAGUCUCCU

3184	976	AUCUUCUUCUUCAGACACAGG

3185	977	AACUACUGCAAACAACCUAUA

3186	978	UCUCUAUGGAUCACCUGGUUU

3187	979	AUUGUACCAAAUGUGAAUCCU

3188	980	UUCUCAAUGCUAAUAGCAUGU

3189	981	AUUUCUUACAGAGUUGAAUGU

3190	982	UAUAUCACCUUUCUCUAGAUC

3191	983	AAUUAAUUUGUCAACAUUUCU

3192	984	UGUUUACUUAAUGUCCAACAA

3193	985	UCAGUUACAACUAAUUUCACA

3194	986	UCUAAUACUUAUUAGAAAUAU

3195	987	ACGUACACUAUAUAGUUUGCU

3196	988	UGCAACAGAUGUUAUCAAGGG

3197	989	UUCUGGAGCUCUGGAGUUCCA

3198	990	UUACAUGAAUACAAAUUUAUA

3199	991	UUAUGGUCACUUCAACAUUGC

3200	992	AAGUCAUAUAAGGAAUUCUGU

3201	993	UAACUGCAAGUAGCUUAGAUA

3202	994	ACAGUUAUAUUCUAGCAAGUG

3203	995	AAGUGGUUUGGAGCUGUGGUU

3204	996	UCUGAGGUGACUACCUCAUUA

3205	997	AACACUCACAAUGCUUCUUAG

3206	998	UAUAACAAUAUCAAAUAAAAU

3207	999	ACACACAUUGAACUUGAAUUU

3208	1000	AAUAGCAUGUAAUUACUUUUU

3209	1001	UUAUUAUCAAAUCUUGGUACA

3210	1002	AAAGAAUAAAUACUUGAGUUA

3211	1003	CUGAAUUUCAGUCCUCUUGUU

3212	1004	AUGAACUUCAUUUGCUUGAGU

3213	1005	ACAUCCAUCUCAAGACAGCGA

3214	1006	UAUUUGGUACUGCUGGUGAAG

3215	1007	AGGAUUUCAUUGAAUUUCCCG

3216	1008	UUAGAUAAAGACCAAGAGAUU

3217	1009	AAGAGACCAGAUAUCAACUUU

3218	1010	AUCAUCUUACAUAGUUCUUUU

3219	1011	AUAACACAAAUUGUUAGUUUU

3220	1012	CACUUCAACAUUGCUGCCCUG

3221	1013	AGACAGUCCUACAUAUUUGUU

3222	1014	UAGUGCUGUAUAAACAGUACC

3223	1015	UAUACUGCAAAUUAAGAAGCC

3224	1016	AUUUAGGUAUCAUUAUCUUUG

3225	1017	AAACAGAAAUAGGUGAUACAU

3226	1018	UCUUCUUCCUCUUCAUCUUCU

3227	1019	UCAUUUCUCUCUGCAACUUGU

3228	1020	AAUAAUUGUAACUAGCAAAUA

3229	1021	AACUUCAUUUGCUUGAGUUUU

3230	1022	UGUUCACACAGUACUUGCUCU

3231	1023	UAUCCAGACCGUCAGACAUUU

3232	1024	AAAGCUCAUGUAUUUCUGGUU

3233	1025	UCACGGAAUACAGCUGACAGU

3234	1026	UGGAACCAUACCAUCAGCAGG

3235	1027	UUGGAAUCAUAGAAUUUGAGA

3236	1028	UAAACACGUACACUAUAUAGU

3237	1029	CACAACACUAUGAAGAGGGAG

3238	1030	CACACUAGCAACAUCAAAGAU

3239	1031	UCCAUCUUUCCUGCAGCAGAG

3240	1032	AUAUAAGGAAUUCUGUCGGAC

3241	1033	CAACAUUAACGUUCUUUCCUU

3242	1034	UGGUGUGACCUCUUUAUUUGG

3243	1035	AUAAAGAAUAAAUACUUGAGU

3244	1036	UAUACAUAACUCUCCAAUACA

3245	1037	UGUUGGGUUAUAUUCAUUUGG

3246	1038	UCCUAUGAGGAUUUCCUAGGU

3247	1039	UUCUAAAGGAGACUCCGAUGG

3248	1040	UCCUGAUGUAAAGCUCAUGUA

3249	1041	AUUUCAUUGAAUUUCCCGGCA

3250	1042	AAUCUCUACUGUGCUUCUCAC

3251	1043	AUCUGUCCUUCAUCCAUACAG

3252	1044	AUCUCCUGAUGUAAAGCUCAU

3253	1045	UCCAGCAGUGUACUCAUCAUA

3254	1046	UGCAUGGGCUCUGCUAUCUUG

3255	1047	AAUGCUAUCUUUGGUUCCCAA

3256	1048	AUGCUGAAUUUCAGUCCUCUU

3257	1049	UCUCCUGAUGUAAAGCUCAUG

3258	1050	UACCCAUAGUUCAUCACCCAC

3259	1051	UACAUAUUUGUUUAAUGAUUU

3260	1052	AUGGAAUGUGCUUCACCGGGG

3261	1053	UCUGCCUACAGUGAUCUGAAG

3262	1054	CAAGUCAUAACUUCUAUUGAA

3263	1055	CUUUCUUAUUCUUCUCUUCAG

3264	1056	ACACACAAGCACACACAUUGA

3265	1057	UGCAAAUUAAGAAGCCUUCUA

3266	1058	UCAUUAUCUUUGUUUACUUAA

3267	1059	AAUCUGAAUAACAUAAAGAAU

3268	1060	UAAAUGUGGUUUCUCCUAUGA

3269	1061	UCCUCUUUCAGGUAUUAAGGA

3270	1062	AACACUAUGAAGAGGGAGUGU

3271	1063	UAAUAUUACCGUUUCAUUUUC

3272	1064	UCAUCAGAAAUGCUAUCUUUG

3273	1065	UUAUUUCCAAGUUCCCAUUUA

3274	1066	UAUCCUUCUAGUCCUCCAAAA

3275	1067	UUCCCAACAAAUUAAUUUGUC

3276	1068	AUCCUCGCCUAUCCACAUCCA

3277	1069	UUAUAUCUCUAUGGAUCACCU

3278	1070	CUUUGUUUACUUAAUGUCCAA

3279	1071	AUUGAAAGAUGUGCCCUCGUU

3280	1072	UAUUCCUAACUCAGGACAUUU

3281	1073	CUUCUCUAGGUAUAGGGUCUG

3282	1074	UCACCUUUCUCUAGAUCUUUA

3283	1075	AACUUAUAGAUAAUAGUCUCC

3284	1076	UGGACACACAAAUAUUUACAA

3285	1077	UUCUUCAGACACAGGAGGGGC

3286	1078	UCUCGAACUCCUGACCUCAGG

3287	1079	UUGCAAGUUCAACCCAAUUAA

3288	1080	UGUGAAGAUCUUAUCAUCAAU

3289	1081	UCAUUAUUAAAGUUCUCACCU

3290	1082	AUUAUGGGAUAGCAUUUGCCU

3291	1083	AAAUACACGUUCAGAAUUGUG

3292	1084	AGCUUGUGGGUUCUUCUUCUG

3293	1085	UAUUUACACGAUCUUUGAGCU

3294	1086	UGAAUUUCAGUCCUCUUGUUC

3295	1087	UCUCUGUGACCACAUCAGUCA

3296	1088	UAAAUGAAUUGGAAGGCUGCC

3297	1089	UCAGAUACAAUGCCCUGAGUG

3298	1090	CAAGCACACACAUUGAACUUG

3299	1091	UGCUGUUGAAGGUUCAUCUGC

3300	1092	UUCCCACCAUAGUGCUUCGUU

3301	1093	UGUUAUGUUGGAAGUUUGGAG

3302	1094	AUUAUCCAGACCGUCAGACAU

3303	1095	UUGAAUGUUUACUAUAUCACC

3304	1096	AUGAAUAGGGCUUCCUAACCA

3305	1097	AGCAACAUCAAAGAUUUGGAU

3306	1098	UGAAAUUAGUGGGACUUGCCC

3307	1099	UAACCAGGUAUUGGGCUCUCU

3308	1100	UCAAUAAUGAAUAUGGUAUUU

3309	1101	AAGAAGUUUCUAUUCAUUUGA

3310	1102	UGGAGACGAAGUUUCACUCUU

3311	1103	CAACAUAAGAGACUCAGGCUU

3312	1104	UAAAUAAUUUGUAUCAUAAGU

3313	1105	UAAUAUCCUGUUGGACAAGAA

3314	1106	GAAUCCUUCAGCAUCACUGUG

3315	1107	UGCAGAUUCAGUUAGACAUUG

3316	1108	UAUUAUAGAAUCUCUCAGAAC

3317	1109	AUUGGGACCAUCCACUAACUC

3318	1110	AAAUAUUCCAUUAUUUCCAAG

3319	1111	AGAAAUAGGUGAUACAUAGGA

3320	1112	UCUAUUGCUUCAACCACAAUU

3321	1113	UUUAUUUAUUGUAAAGCAAUA

3322	1114	UUUAAUCCAAAGUUACAGAAG

3323	1115	CAAGUUACUCGAUUGUACCAA

3324	1116	AUAAGCACAAGAGAGGAUUAA

3325	1117	UCAGCCUCCCAAGUAGCUGGG

3326	1118	AUUUCUCAAUGCUAAUAGCAU

3327	1119	AAGACCCUAAGGAUCAUCUAG

3328	1120	GAGAAGAAUAUUGUCACUCUU

3329	1121	UCUAUAACACAAAUUGUUAGU

3330	1122	UCACUGCUCCAAGGUCUCCAA

3331	1123	AUUUGGUCACUUAAAGGAGUG

3332	1124	UCCUUCAUCCAUACAGGUCUC

3333	1125	CUACAUCUGACUCAUUCUCUA

3334	1126	UCUUCCAUCUUUCCUGCAGCA

3335	1127	ACUGCAACAUAAGAGACUCAG

3336	1128	AAGCAAUGGAUUCAACCACAG

3337	1129	CUCUGUGACCACAUCAGUCAG

3338	1130	AUCCCGGUUGUUACUAUUCAU

3339	1131	AGAAGAUUCAGGAAGUGCCAA

3340	1132	AAGCCCAGCACUACUUCACAG

3341	1133	AAAUGUGGUUUCUCCUAUGAG

3342	1134	AUCUAAAUAAUUAACAAUAUU

3343	1135	UAUCUCUGCCCUGCAUGCUCU

3344	1136	AUUAAACACAUUCCCAAUGCA

3345	1137	UAGUAUGCUUCAAAUUAAUAU

3346	1138	UCCUAAGAAAGCGUGUGCCAU

3347	1139	AGAAGGAUGGAACCAUACCAU

3348	1140	UUAGGGCAUGGACUUCCACAU

3349	1141	AAACUCUAGAAAGCCCAGCAC

3350	1142	AACAUGGUGACUGAUUUGAGG

3351	1143	AAAUAAUUUGUAUCAUAAGUA

3352	1144	CUUAACUGAAUAUUAACUGCA

3353	1145	AGAAAUAAACCCAUUGAGCAA

3354	1146	UAGAAAGCCCAGCACUACUUC

3355	1147	UCCUGUUGCAAUGUCUAGUGC

3356	1148	AAGAAGCCUUCUAUAACACAA

3357	1149	CACAUGUUCACACAGUACUUG

3358	1150	CAUUAUUAAAGUUCUCACCUA

3359	1151	UUGUUACUAUUCAUCCUCAGU

3360	1152	UGGGAAGAUAGAGCGAAGCCU

3361	1153	AGAAUACUCGUACACACAGGU

3362	1154	UCUUCCUCUUCAUCUUCUUCU

3363	1155	UCAUGCACAAUCCAUAUUUCA

3364	1156	AACUAGCAAAUAUCUCUGCCC

3365	1157	UUUCUCUUCAUUAUCCAGACC

3366	1158	AAUGCUAAUAGCAUGUAAUUA

3367	1159	UCAGAGCUCAGAGACUGGGAG

3368	1160	UUUGGAGUUCUAAUAGUGACA

3369	1161	UCACUGACCUCCCAUUUCUUA

3370	1162	UAAUGUCCAACAAGGAUUUCA

3371	1163	UCCUUCUUCUUAUUGGUUUUA

3372	1164	UGCAAGUCAUAACUUCUAUUG

3373	1165	UAAGAUGUGGAUAUAUGGAUG

3374	1166	ACGUGGAUCCUUCUCAACUUG

3375	1167	AAUACUUGAGUUAAAUCUUCU

3376	1168	AGUGUACUCAUCAUACAACUG

3377	1169	UCUCAGGAUUCUGGAGCUCUG

3378	1170	UCCUACCUGAAUGAUAUACAG

3379	1171	AUAGGGCUUCCUAACCAGGUA

3380	1172	AUAUAUGGUGAAAUAGUAGUC

3381	1173	AGUGAUAUUAUAGAAUCUCUC

3382	1174	AUGUAUCUAUUUCCUCCUGGU

3383	1175	AAAGUCAGUCAAUUUAACAGA

3384	1176	UUUGGGCUGCGAUUCAGGCUU

3385	1177	UCUUUGUCCAUAUGCAUUUCU

3386	1178	UUUGAAUGCAAGAGGGACUAC

3387	1179	AUUUAUUGUAAAGCAAUAUUA

3388	1180	UUUCUGCUGUUUAUUUAUUGU

3389	1181	AAUAUCUCUGCCCUGCAUGCU

3390	1182	UUUGUUUACUUAAUGUCCAAC

3391	1183	AUAUGGUAUUUGCGGGUCCAU

3392	1184	AUUAUUAUCAAAUCUUGGUAC

3393	1185	UAAAUGCUACAAGUUGUAUAG

3394	1186	AUAGUUUGCUGAAACUCUAAA

3395	1187	UGCUAACUAAUGAAUAGGGCU

3396	1188	UUCCAGAAAGGCAAUAUCUGC

3397	1189	AGAACCUGAACUCACCUAGCA

3398	1190	UGAUGAUUAAUGUAUCUAUUU

3399	1191	UCCGAAACAGAAAUAGGUGAU

3400	1192	UUGUCAUCAGAAAUGCUAUCU

3401	1193	UUUGAAAGGUAAAGAACCCCC

3402	1194	CUUAGAGAAACAACUUUCUGU

3403	1195	AUAUCAUUUAUAGACAAAUAU

3404	1196	AGGAUUUCACCGUUUGAGCUU

3405	1197	UAGUGGGACUUGCCCUAUUGG

3406	1198	AUAUUUGUUUAAUGAUUUCAA

3407	1199	UCACAUAGCAAUUUAGUAAUA

3408	1200	GAAUACUCGUACACACAGGUG

3409	1201	UUCCACAUGUUCACACAGUAC

3410	1202	AACCUGAACUCACCUAGCAGG

3411	1203	UCUUACAGAGUUGAAUGUUUA

3412	1204	UACUUCACAGGAAAGGAGAAG

3413	1205	CAACUUGUAAGUGUUUAGGUU

3414	1206	GCUAACAACAUUAACGUUCUU

3415	1207	AUUCAGUUAGACAUUGUUUAA

3416	1208	UACAAAGUGGUAGUAAAGAAG

3417	1209	UACAUAAGUUCUGUUUAGAUU

3418	1210	AAAUAUACAUAACUCUCCAAU

3419	1211	UGUCCUUCAUCCAUACAGGUC

3420	1212	AUGCUCUGGUCUUGGUGCGAU

3421	1213	AGUAUUCUACAUUUAUCUGGU

3422	1214	AUAAACAGUACCUGAUGCCCC

3423	1215	UCAUCUCCUGAACAUAAACAC

3424	1216	UAGUAUUUAUCCCACUACAUC

3425	1217	AUCCCACUACAUCUGACUCAU

3426	1218	CAUAGAAUUUGAGAACAUCUA

3427	1219	UACACACAGGUGUGCACAUGG

3428	1220	AACGAAGUCAUUACCCAACAU

3429	1221	UUGAGUGCAGGAAAUCCAAAG

3430	1222	UAGGCAGGGCAUUGGGACCAU

3431	1223	AUGUGAAUCCUUCAGCAUCAC

3432	1224	ACACACAGGUGUGCACAUGGA

3433	1225	UCAUAGGAGAAAUAUUCCAUU

3434	1226	UCUGCUGUUUAUUUAUUGUAA

3435	1227	CUUCAAAUUAAUAUUACCGUU

3436	1228	UCUCUGGGCGCUCUUUCUCCU

3437	1229	UCCUAGGCUAGUAUUUAUCCC

3438	1230	UUUCUCUGCCUACAGUGAUCU

3439	1231	CAACAUUGAAAGAUGUGCCCU

3440	1232	UUCUUAGCUUCUCUAAGAUCU

3441	1233	ACAGUCUCUCAGGAUUCUGGA

3442	1234	UGGUUUACUCAAUUAUCUUUU

3443	1235	AGUUCUAAUAGUGACAUCUCC

3444	1236	ACCACACACAAGCACACACAU

3445	1237	UCUCUAUGUUGGUCAGGCUGG

3446	1238	UCAAAGUCUGAAGGAAGAGAG

3447	1239	AGACCAAGAGAUUCAACCGGG

3448	1240	UUCACCUUCCACCAUUUCAAU

3449	1241	CAAAGUAUAACAUAGUAUGCU

3450	1242	UAGCUACAGGAUUCUGUGAAG

3451	1243	AAUAUCUGCAACAGAUGUUAU

3452	1244	ACAAUGACACACACACGAGAU

3453	1245	AAGUUUCACUCUUGUUGCCGA

3454	1246	AACAUUGAAAGAUGUGCCCUC

3455	1247	UCUGCAACAGAUGUUAUCAAG

3456	1248	GUGGUAGUAAAGAAGUACCUG

3457	1249	AUGCUUCUUAGCUUCUCUAAG

3458	1250	UGCUGAAGAAUCCCGGUUGUU

3459	1251	ACUACAUCUGACUCAUUCUCU

3460	1252	UUCGCUUCACGGUGGAAGUGA

3461	1253	AAGCUCAUGUAUUUCUGGUUG

3462	1254	UCUCCUCAUCUGUCAUCUUGG

3463	1255	AUUACAUAAUCUGAGGGAGUA

3464	1256	AUUCUCUACUAUCGCUGUUGA

3465	1257	AUCACAUUGGGUAAGGAGUUU

3466	1258	UUUCUUUGGUGAGUUAGAAGG

3467	1259	CAAUUUAGUAAUAAAGCUCAU

3468	1260	AUUGCUGCCCUGUUUGGGCUG

3469	1261	AUCUUUGUUUAAAUGUGGUUU

3470	1262	ACAGGAAGCAAUUUCGUGUUU

3471	1263	UUCAAGCGAUUCUCCCACCUC

3472	1264	AUACAGGUCUCUGUGACCACA

3473	1265	AAACAACUGUAAAUGAAUUGG

3474	1266	UAACAACCUGGUUUACUCAAU

3475	1267	AUAGUUGUAAUCCCUGUUUAU

3476	1268	GAACCUGAACUCACCUAGCAG

3477	1269	AUGAUGAUUAAUGUAUCUAUU

3478	1270	AAGAGAGGAUUAAUUUAGGUA

3479	1271	GUUUACAGAUAACACAUUCUG

3480	1272	UAUCUAUUUCCUCCUGGUAUG

3481	1273	AUAGAUAAUAGUCUCCUAAGA

3482	1274	UAUCCCACUGUGGACAUUUUC

3483	1275	UUGAAUUUCCCGGCACUAUGA

3484	1276	AAUUUAGUAAUAAAGCUCAUA

3485	1277	UUGCAUCCCAGGAUUUCAUUG

3486	1278	UCUUUCCAGCAGUGUACUCAU

3487	1279	UACCAUCAGCAGGUCUACAAA

3488	1280	UCAUCUUCUUCUUCUUCUUCC

3489	1281	AUCCAUACAGGUCUCUGUGAC

3490	1282	UAGCAAAUAUCUCUGCCCUGC

3491	1283	UCAGGUGAUCCGCCUGCCUUG

3492	1284	AGAGACUCAGGCUUAAACGUG

3493	1285	UCUGUGAAGAUCUUAUCAUCA

3494	1286	UUAUUAGAAAUAUACAUAACU

3495	1287	AGCUUCUCUAAGAUCUCCUCA

3496	1288	AACCACAGAACGAGUAUAGAU

3497	1289	UCAGGAUUCUGGAGCUCUGGA

3498	1290	UACAAAUAAAUUACAUAAUCU

3499	1291	UCAUUAAUAAUUAAUUCCUUC

3500	1292	UAAUUGUAACUAGCAAAUAUC

3501	1293	UUAAGGCCUCUCUCUCUCAUU

3502	1294	CAUUUCUCUCUGCAACUUGUA

3503	1295	UCUAAAUAAUUAACAAUAUUA

3504	1296	ACAACCUAUAAAUAGGCAGAA

3505	1297	UUGGGCUGCGAUUCAGGCUUA

3506	1298	AAGAGAAUAAACUGUUAACAA

3507	1299	AUUUGUAUCAUAAGUAAAUGA

3508	1300	UGCAACAUAAGAGACUCAGGC

3509	1301	UUAGUGGGACUUGCCCUAUUG

3510	1302	AUGGAACCAUACCAUCAGCAG

3511	1303	CCAGUAGACAUCACUACCCUG

3512	1304	UCCCAUUUAUUUCCUUCCCAG

3513	1305	GAACUAAGCAUGAACACACCA

3514	1306	CUUUAUUUGGUACUGCUGGUG

3515	1307	AAUAAAUUACAUAAUCUGAGG

3516	1308	UUCCAUUAUUUCCAAGUUCCC

3517	1309	AUCAGCAAGAACGAAGUCAUU

3518	1310	CUAACAACAUUAACGUUCUUU

3519	1311	AACAGAACUAUAACUGAAUGC

3520	1312	ACAAAUUAAUUUGUCAACAUU

3521	1313	UCGUACACACAGGUGUGCACA

3522	1314	GUUCACACAGUACUUGCUCUG

3523	1315	ACACGUACACUAUAUAGUUUG

3524	1316	AAAGACCCUAAGGAUCAUCUA

3525	1317	UUACAGGCCCAGAUUCGUUUU

3526	1318	CUCAAGUACAGUUAUAUUCUA

3527	1319	UGGAAAGACCCUAAGGAUCAU

3528	1320	AAAGGCAAUAUCUGCAACAGA

3529	1321	CAUGAACACACCAUAUUCCGA

3530	1322	ACUUAAAGGAGUGUGGAUCAG

3531	1323	UUGCAGGCACUCUCUGCAGAC

3532	1324	UGUUUGGAGUUCUAAUAGUGA

3533	1325	UGACAUUUCUUGGGAUAUGAU

3534	1326	UUCACUCUUAGCAGUCUCAGC

3535	1327	UACAAAUGCUGAAUUUCAGUC

3536	1328	AAAUAAUCUCUACUGUGCUUC

3537	1329	AAGAAUAAAUACUUGAGUUAA

3538	1330	UCACAGUUUCAGUUUCAGUGU

3539	1331	ACUACUGCAAACAACCUAUAA

3540	1332	AUUGGGAUGUAGCCUUCACUG

3541	1333	AAGUAGCUUAGAUAAAGACCA

3542	1334	AAUGAUGAUUAAUGUAUCUAU

3543	1335	ACAGGAUUCUGUGAAGAUCUU

3544	1336	UAGGUCCAAGUUUCAAACUGC

3545	1337	AGCUUCUAAAGGAGACUCCGA

3546	1338	AAUCACUGUGGGAGUUGUCAU

3547	1339	UAAACUCUAGAAAGCCCAGCA

3548	1340	UCAGGCUGGUCUCGAACUCCU

3549	1341	AUGUCCAACAAGGAUUUCAGU

3550	1342	UUUGGAGCUGUGGUUGAGUGC

3551	1343	CAGGCUGGUCUCGAACUCCUG

3552	1344	UGAAUCGUAUGCUCAAAGUCU

3553	1345	UCACCGUUUGAGCUUUAUUUA

3554	1346	AAUCGUGCCCAUUGCUCUGGA

3555	1347	GAAUGUUUACUAUAUCACCUU

3556	1348	UGUAUCAUAAGUAAAUGAUGA

3557	1349	UAACAAUAUUAGGGUUCUUAU

3558	1350	CUGAAUUUGCAAGGCAACCUA

3559	1351	UUGUAAAGCAAUAUUAUAACA

3560	1352	UACCCUCUUUCCAGCAGUGUA

3561	1353	AACAAUAUUAGGGUUCUUAUU

3562	1354	AAUUAAUUCCUUCUUGGGUUG

3563	1355	UCAGAGACUGGGAGAUACUUG

3564	1356	CAAGUUGUAUAGAAUACUCGU

3565	1357	UUCUCUCUGCAACUUGUAAGU

3566	1358	UCACAAUGCUUCUUAGCUUCU

3567	1359	UGUCCAUAUGCAUUUCUUUUU

3568	1360	AACAUAAGAGACUCAGGCUUA

3569	1361	UUGAAAUUAGUGGGACUUGCC

3570	1362	UCCUUCCCAGUCCACAUGCAA

3571	1363	AAUAUUAAACACAUUCCCAAU

3572	1364	UGUAUAGAAUACUCGUACACA

3573	1365	CUGUUGAAGGUUCAUCUGCUU

3574	1366	UAGGAGAAAUAUUCCAUUAUU

3575	1367	CACACAUUGAACUUGAAUUUU

3576	1368	GUUGUUACUAUUCAUCCUCAG

3577	1369	ACAGAGUUGAAUGUUUACUAU

3578	1370	UUCACCGUUUGAGCUUUAUUU

3579	1371	CAAUGGAAUGUGCUUCACCGG

3580	1372	UGUUGGUCAGGCUGGUCUCGA

3581	1373	UGUCCUGUUGCAAUGUCUAGU

3582	1374	CUUCUAUUGAAAUUAGUGGGA

3583	1375	UAUAUUCUAGCAAGUGUGACA

3584	1376	UAAAGGAGUGUGGAUCAGAAA

3585	1377	UUGCUGAAACUCUAAAGAAAG

3586	1378	UUUCUAAUACUUAUUAGAAAU

3587	1379	UUUGCUUAACUGAAUAUUAAC

3588	1380	UUCACGGUGGAAGUGACCACU

3589	1381	AGGUCUCUGUGACCACAUCAG

3590	1382	UGACAACGCACUGGAUCCUUG

3591	1383	UCCUCUUCAUCUUCUUCUUCA

3592	1384	AUACAGACAACAGGAAGCAAU

3593	1385	GAUGUUAUGAGUAUAAUCCCA

3594	1386	AUUUAUCCCACUACAUCUGAC

3595	1387	AUAUAUGGAUGGUUAGAUGGA

3596	1388	UAAGUAAAUGAUGAUUAAUGU

3597	1389	AUUAUCUUUGUUUACUUAAUG

3598	1390	CAGAACUAUAACUGAAUGCCA

3599	1391	AAAGCAUAAGAGAGAAGCCAU

3600	1392	AGAAGUUUCUAUUCAUUUGAA

3601	1393	AAUUAUUUACACGAUCUUUGA

3602	1394	UGCUGAGGUCAGAAGGAUGGA

3603	1395	AAAUUAAUAUUACCGUUUCAU

3604	1396	UCAUUGAAUUUCCCGGCACUA

3605	1397	UUAUUUACACGAUCUUUGAGC

3606	1398	UUGGAUGCUGAGGUCAGAAGG

3607	1399	UUUAAUGAUUUCAAAGUCAGC

3608	1400	AAGUUCAACCCAAUUAAGUGG

3609	1401	AAAUGAGAUACAAUUCUGAUA

3610	1402	GUAGCCUUCACUGACCUCCCA

3611	1403	AGGAUGGAACCAUACCAUCAG

3612	1404	AUCCUUGCUAACAACAUUAAC

3613	1405	UUCAGGCUUACAAAUAAAUUA

3614	1406	UCUUGUCCUGUUGCAAUGUCU

3615	1407	ACAGACAACAGGAAGCAAUUU

3616	1408	UUACAGAGUUGAAUGUUUACU

3617	1409	AACAACAUUAACGUUCUUUCC

3618	1410	AUCUGAGGUGACUACCUCAUU

3619	1411	AAUCCCAGUAGACAUCACUAC

3620	1412	AAGUAUUUCUGUAUUGAGAAU

3621	1413	AUUAAUAUUACCGUUUCAUUU

3622	1414	UAUCCUUUGGUUAGAUGGUCU

3623	1415	AGAAGAAUAUUGUCACUCUUU

3624	1416	CUUCUUCUUCUUCUUCCUCUU

3625	1417	UCAUUAGAAAUAAACCCAUUG

3626	1418	UUAUAGACAAAUAUCUCAAAC

3627	1419	AACUGAAAGCAUAAGAGAGAA

3628	1420	AUUUCAGUAUUCUACAUUUAU

3629	1421	AUCAUUUAUAGACAAAUAUCU

3630	1422	UCAUAACUUCUAUUGAAAUUA

3631	1423	CAUAACUCUCCAAUACAGGGA

3632	1424	AAAUAGGUGAUACAUAGGAAA

3633	1425	AUCACAACUACUGCAAACAAC

3634	1426	AUGAAUCGUAUGCUCAAAGUC

3635	1427	UGGAGUUCUAAUAGUGACAUC

3636	1428	UAUUUAUUGUAAAGCAAUAUU

3637	1429	CAAAUGUGAAUCCUUCAGCAU

3638	1430	AUUGCUCUGGAAUUCCAGUGA

3639	1431	AUUUCUGGUUGUUGACUGUUU

3640	1432	GUAUUUAUCCCACUACAUCUG

3641	1433	UUCCCAGUCUUUGUCCAUAUG

3642	1434	CUAAUAGUGACAUCUCCCUAG

3643	1435	UGUUUAAAUGUGGUUUCUCCU

3644	1436	UUCCUCUUGGGUACUAAAUCU

3645	1437	AGCAGUGUACUCAUCAUACAA

3646	1438	UCGUUAUCUCAGGGCACACUA

3647	1439	CUCUACUGUGCUUCUCACCCU

3648	1440	GUAACUAGCAAAUAUCUCUGC

3649	1441	UGGUGAGUUAGAAGGAAGUUA

3650	1442	CAAUGCUUCUUAGCUUCUCUA

3651	1443	AUAAAUAAUUUGUAUCAUAAG

3652	1444	AAGUUCUGUUUAGAUUCUUUU

3653	1445	CAACGCACUGGAUCCUUGCUA

3654	1446	UGAUUUCAAAGUCAGCUUUUA

3655	1447	UAAAGCACACCACACACAAGC

3656	1448	UUGCGGGUCCAUAAAGCACAC

3657	1449	UUUGAGCUUUAUUUAGAUAUA

3658	1450	AUGGAAUAAUUGUAACUAGCA

3659	1451	UUGCUUAACUGAAUAUUAACU

3660	1452	CACAGUUUCAGUUUCAGUGUG

3661	1453	AUCGUGCCCAUUGCUCUGGAA

3662	1454	UCACGGUGGAAGUGACCACUU

3663	1455	CUAAAUCUGUUGAACAUGUUG

3664	1456	AGCAAUUUAGUAAUAAAGCUC

3665	1457	UGGGAUAUGAUUGUAAGUUAA

3666	1458	UAGCAGGCUGAAUUUGCAAGG

3667	1459	UACAGUGCAUAUGUUUCAUAA

3668	1460	UUCAAAUCCCAGGCCCAUCAA

3669	1461	UUCUCCCACCUCAGCCUCCCA

3670	1462	UUAAAGGAGUGUGGAUCAGAA

3671	1463	UAGAUAAAGACCAAGAGAUUC

3672	1464	UCAACAUUGCUGCCCUGUUUG

3673	1465	UCCAUAAAGCACACCACACAC

3674	1466	UGCAACUCUAUUAGGGCAUGG

3675	1467	AUGUUUACUAUAUCACCUUUC

3676	1468	UGAAGGUUCAUCUGCUUUAUG

3677	1469	UAGUUGUAAUCCCUGUUUAUG

3678	1470	GAUCUUAUCAUCAAUAAUGAA

3679	1471	AUGGAGAGGUUAAGUGACUUG

3680	1472	UAUGGAAUAAUUGUAACUAGC

3681	1473	AUGCAUGGGCUCUGCUAUCUU

3682	1474	UCGAUUGUACCAAAUGUGAAU

3683	1475	CAUAUCUGAGGUGACUACCUC

3684	1476	AAGAACUAAGCAUGAACACAC

3685	1477	UUUAUCCCACUACAUCUGACU

3686	1478	AUUCCAUGACUACCCAUAGUU

3687	1479	UAAACACAUUCCCAAUGCAUG

3688	1480	AUUCAUUUGAAAGGUAAAGAA

3689	1481	AUAGGAGAAAUAUUCCAUUAU

3690	1482	UCUUAGCGGCUGCUGUUCUUA

3691	1483	UAUGCUUCAAAUUAAUAUUAC

3692	1484	UGGAUGGUUAGAUGGAUGGAU

3693	1485	AAAGAACUAAGCAUGAACACA

3694	1486	AAGGAGGUUUGAAUGCAAGAG

3695	1487	UCUAUGGAUCACCUGGUUUGA

3696	1488	AUGGAUGGUUAGAUGGAUGGA

3697	1489	ACACACCAUAUUCCGAAACAG

3698	1490	AUGGUUAGAUGGAUGGAUGUA

3699	1491	AGAUACAAUUCUGAUAAACAA

3700	1492	AGUAGCUAUCUAAAUAAUUAA

3701	1493	UCCACAUGCAAAUACACGUUC

3702	1494	AGUUACAGAAGAAUUUCACUA

3703	1495	UUGAAUGCAAGAGGGACUACU

3704	1496	CAGGAUUCUGUGAAGAUCUUA

3705	1497	CUGAACACACAUAUUCCUCUC

3706	1498	ACUCAAGACACAGUCAUGCAC

3707	1499	AUUAUAACAAUAUCAAAUAAA

3708	1500	UCUUUCAGGUAUUAAGGAGAU

3709	1501	UCCCAUCUUUGUUUAAAUGUG

3710	1502	AAUUGUAACUAGCAAAUAUCU

3711	1503	AACUAAGCAGCAUAUCUGAGG

3712	1504	AGAUGUAAGGAUCAGGUGGUU

3713	1505	AAUUAGUGGGACUUGCCCUAU

3714	1506	AGUUUGGAGUAAUCGUGCCCA

3715	1507	CAAAUCUUGGUACAAAGUGGU

3716	1508	ACUUUGCUCAGGAGUGAUCUG

3717	1509	UCUUCAAAGUGAAUGCACAAA

3718	1510	AUUAUUUCCAAGUUCCCAUUU

3719	1511	UCAACAUUUCUCAAUGCUAAU

3720	1512	AGGAGGUCAAGCCUCUCCCAA

3721	1513	AGUAGACAUCACUACCCUGUG

3722	1514	UGACAGGAUUUCACCGUUUGA

3723	1515	UCUUCCUAGGCUAGUAUUUAU

3724	1516	UCAACAUGUAAGGGAUGCUAA

3725	1517	CAUCUUCUUCUUCUUCUUCCU

3726	1518	UAAUAGUGACAUCUCCCUAGC

3727	1519	GCUUAGAGAAACAACUUUCUG

3728	1520	CAUCUAGAACAGCUUGUGGGU

3729	1521	UCUUCAUCUUCUUCUUCAGAC

3730	1522	AAAUGCUACAAGUUGUAUAGA

3731	1523	UUUGGUUCCCAACAAAUUAAU

3732	1524	UAUCAACUUUCGGACCAUAAG

3733	1525	AAGCUUGCAGGCACUCUCUGC

3734	1526	CUAUGUAUCCAUGUGCACUUU

3735	1527	AUGGGAUAGCAUUUGCCUGAU

3736	1528	UAAAGCCUAUGGAAUAAUUGU

3737	1529	UAGCUGGGAUUACAGGCGCCC

3738	1530	UCAGGAGUGAUCUGGGCACAG

3739	1531	AGUGCUUCGUUUACUUUGCUC

3740	1532	UCGUUUACUUUGCUCAGGAGU

3741	1533	UCACUCUUAGCAGUCUCAGCC

3742	1534	UAUGAGGAUUUCCUAGGUUCA

3743	1535	UAAUUUGUAUCAUAAGUAAAU

3744	1536	AUUAAUGUAUCUAUUUCCUCC

3745	1537	ACACAACACUAUGAAGAGGGA

3746	1538	AAAUGAAUUGGAAGGCUGCCA

3747	1539	AAGUAGCUGGGAUUACAGGCG

3748	1540	CAUCUAAUGACAAUGCAAGUG

3749	1541	UCUAUGUUGGUCAGGCUGGUC

3750	1542	CUGAGUUCACUUCAAAUCCCA

3751	1543	UCAGAGAAAGUCCCAUCUUUG

3752	1544	AUCCUCAGUGGAGGAGCCGGG

3753	1545	AAGCAAUUUCGUGUUUCUUUU

3754	1546	AUGAGAUACAAUUCUGAUAAA

3755	1547	UACAUAAUCUGAGGGAGUAGG

3756	1548	UCUUUGGUUCCCAACAAAUUA

3757	1549	UGAAGAUCUUAUCAUCAAUAA

3758	1550	AUAUUGUCACUCUUUAUAUCU

3759	1551	UGGUUUACAGAUAACACAUUC

3760	1552	UCUUCUUCUUCCUCUUCAUCU

3761	1553	CUGUCGGACUGACAUUUCUUG

3762	1554	CUCCUCAUUGUUAAUAUGCUG

3763	1555	AAAGAAAUCUGAAUAACAUAA

3764	1556	GACACAGUCACUAAUGUACUG

3765	1557	UGGGUUCAAGCGAUUCUCCCA

3766	1558	AACCAUACCAUCAGCAGGUCU

3767	1559	GUAUAACAUAGUAUGCUUCAA

3768	1560	AUACUUUAGGUCCAAGUUUCA

3769	1561	ACAUGGUGACUGAUUUGAGGG

3770	1562	UGUUUAGGUUCACUCUUAGCA

3771	1563	AGAAGGAAGUUAUCCUUUGGU

3772	1564	ACUAAUGAAUAGGGCUUCCUA

3773	1565	UCCAUGACUACCCAUAGUUCA

3774	1566	AAGGAAGAGAGAUCUCUGGGC

3775	1567	UCUAAAGAAAGUGCUUUCAUU

3776	1568	CUGAAUGUACAUAAGUUCUGU

3777	1569	UGUACAAAGUACUGGAAUUGG

3778	1570	GUGUACUCAUCAUACAACUGG

3779	1571	UCCAGAAAGGCAAUAUCUGCA

3780	1572	AAUAUGGUAUUUGCGGGUCCA

3781	1573	AAUAGAUAUAUGGUGAAAUAG

3782	1574	AUUUCCUUCCCAGUCCACAUG

3783	1575	CAGACUUUACAUACAGACUGU

3784	1576	CUUACUGCUGGUAUUAUGGGA

3785	1577	UCAUAAGUAAAUGAUGAUUAA

3786	1578	UCUGUCCUUCAUCCAUACAGG

3787	1579	UGACUUGCCUAGCGUCACAUA

3788	1580	CAUCUGACUCAUUCUCUACUA

3789	1581	AUGAGGGAGAUGGUGAGGUGU

3790	1582	GUACACUAUAUAGUUUGCUGA

3791	1583	UUUCACUCUUGUUGCCGAGGC

3792	1584	UACUGCAAACAACCUAUAAAU

3793	1585	CAACUGAUUUCAAUUAUCUGU

3794	1586	ACAUUGUUUAAUAUUAAACAC

3795	1587	CAGUUAUACAGACAACAGGAA

3796	1588	UUUGCAUCCCAGGAUUUCAUU

3797	1589	UAUCAUUUAUAGACAAAUAUC

3798	1590	UCCCACUACAUCUGACUCAUU

3799	1591	UACAGGCCCAGAUUCGUUUUU

3800	1592	UCUACUCUCAGAAGAUUCAGG

3801	1593	AUUUCAGUCUUACUCAUGAGG

3802	1594	GAAACUAAGCAGCAUAUCUGA

3803	1595	AAGGAAGUUAUCCUUUGGUUA

3804	1596	CUUCUUCAGACACAGGAGGGG

3805	1597	UUAGCGGCUGCUGUUCUUAAU

3806	1598	UUUCACUACACAUGGUUUACA

3807	1599	UGGAACAUGGACACACAAAUA

3808	1600	AUGUCACAGUUUCAGUUUCAG

3809	1601	UUAAUCCAAAGUUACAGAAGA

3810	1602	UCUCCCACCUCAGCCUCCCAA

3811	1603	AAUAGGGCUUCCUAACCAGGU

3812	1604	AGCACAUGGAGACCAUCCCAA

3813	1605	UGCAACUUGUAAGUGUUUAGG

3814	1606	AAGAGACUCAGGCUUAAACGU

3815	1607	AAUAAAGCUCAUAUUAGACUC

3816	1608	UAGCUAUCUAAAUAAUUAACA

3817	1609	AUGCUGAACUGAAAGCAUAAG

3818	1610	AUGAGUAUAAUCCCAGUAGAC

3819	1611	ACUAAGCAUGAACACACCAUA

3820	1612	AGUGCAGGAAAUCCAAAGCUU

3821	1613	UGAUAUCUCAGUUCCCGCAUU

3822	1614	AAUAUUAUAACAAUAUCAAAU

3823	1615	AGUAAUAUCCUGUUGGACAAG

3824	1616	AAUGCUGAAUUUCAGUCCUCU

3825	1617	UCCUCAUUGUUAAUAUGCUGA

3826	1618	UGCAAAGUAUAACAUAGUAUG

3827	1619	CAGACAGCUGCUAUCUGUCCU

3828	1620	AUAGUUCCCUUUCUGCUGUUU

3829	1621	CAGGACACAGUCACUAAUGUA

3830	1622	ACAUAACUCUCCAAUACAGGG

3831	1623	UAUUCAUUUGGUCACUUAAAG

3832	1624	UAUCUGCAACAGAUGUUAUCA

3833	1625	AGAAAUAUUCCAUUAUUUCCA

3834	1626	UGAGGUGUAAGGCUUGCAGUC

3835	1627	UGCCCUAUUCCUAACUCAGGA

3836	1628	UUUCCAGCAGUGUACUCAUCA

3837	1629	AAAGAAAGUGCUUUCAUUUUA

3838	1630	AUCUAAUGACAAUGCAAGUGA

3839	1631	AACUAAUGAAUAGGGCUUCCU

3840	1632	CCUUCUAUAACACAAAUUGUU

3841	1633	UCCAUCUCAAGACAGCGAUUU

3842	1634	AUAUUCCAUUAUUUCCAAGUU

3843	1635	UCACAUUGGGUAAGGAGUUUU

3844	1636	ACCAUAAAUACCUUUAAUCCA

3845	1637	GUGAUCUGGGCACAGAACCCA

3846	1638	AAAGUGCUGGGAUUACAGGUA

3847	1639	AAGAAAUCUGAAUAACAUAAA

3848	1640	AUUGAUUGGGAUGUAGCCUUC

3849	1641	ACUCGUACACACAGGUGUGCA

3850	1642	AUGUGGUUUCUCCUAUGAGGA

3851	1643	UACAUACAGACUGUAUGGAAA

3852	1644	UAUUUCCUUCCCAGUCCACAU

3853	1645	AACUGUCAGUUUACAAAUGCU

3854	1646	AGGUGUAAGGCUUGCAGUCUU

3855	1647	GACACAGUCAUGCACAAUCCA

3856	1648	AGGAGAUUAACAACCUGGUUU

3857	1649	AGAAACAACUUUCUGUAAUUU

3858	1650	UGCUGUAGGCAGGGCAUUGGG

3859	1651	UGUGCCCUCGUUAUCUCAGGG

3860	1652	ACAUAGUUGUAAUCCCUGUUU

3861	1653	UCAGCAAGAACGAAGUCAUUA

3862	1654	AGACAUUUAUGAAUAUGCUUU

3863	1655	UCCAACAAGGAUUUCAGUAUU

3864	1656	AGCAAUUUCGUGUUUCUUUUU

3865	1657	UUCCAUCUUUCCUGCAGCAGA

3866	1658	AAUUUCAAGACAUUUAUGAAU

3867	1659	UUCUAAUACUUAUUAGAAAUA

3868	1660	CUUCUUCCUCUUCAUCUUCUU

3869	1661	UCACUACACAUGGUUUACAGA

3870	1662	UCAACCUGAGAGUCUGUUAAA

3871	1663	UUCCAUGACUACCCAUAGUUC

3872	1664	UGGAUGCUGAGGUCAGAAGGA

3873	1665	ACACAGUACUUGCUCUGGUAU

3874	1666	UUAUCAAAUCUUGGUACAAAG

3875	1667	AUAAAUAGAUAUAUGGUGAAA

3876	1668	CUUCUUCUUCCUCUUCAUCUU

3877	1669	UGCUUCAAAUUAAUAUUACCG

3878	1670	AUAUACAUAACUCUCCAAUAC

3879	1671	UAAUUCCACCACCCUAACACA

3880	1672	AAGGCAAUAUCUGCAACAGAU

3881	1673	UGUUUAAUGAUUUCAAAGUCA

3882	1674	UGAUGUAAAGCUCAUGUAUUU

3883	1675	AUACCAUCAGCAGGUCUACAA

3884	1676	UGACACACACACGAGAUCAGC

3885	1677	CUUCUUUCUAAUACUUAUUAG

3886	1678	AAUUUGAGAACAUCUAGAACA

3887	1679	AGCAGGAUGUCACAGUUUCAG

3888	1680	CACGAGAUCAGCAAGAACGAA

3889	1681	UCUUGUUCAGAGCUCAGAGAC

3890	1682	UUCUCACCCUUCCCUGACUUU

3891	1683	CUGAAUAUUAACUGCAAGUAG

3892	1684	AAUGUACAUAAGUUCUGUUUA

3893	1685	UACUUUGCUCAGGAGUGAUCU

3894	1686	UGGGCGCUCUUUCUCCUUCUU

3895	1687	UCCCAGUUUACCCUCUUUCCA

3896	1688	CACAACUACUGCAAACAACCU

3897	1689	UGCAGUCUUAGCGGCUGCUGU

3898	1690	ACUGAAUAUUAACUGCAAGUA

3899	1691	UCACUUCAAAUCCCAGGCCCA

3900	1692	AGGGAUAGAUGUAAGGAUCAG

3901	1693	UUGGAGUAAUCGUGCCCAUUG

3902	1694	UCUGAAUAACAUAAAGAAUAA

3903	1695	UGAGCAAAGGAAUAUAAUUAU

3904	1696	UGAGGUGACUACCUCAUUAUU

3905	1697	AGAGACAGUCCUACAUAUUUG

3906	1698	UUUCUCCUAUGAGGAUUUCCU

3907	1699	UGUUCAGAGCUCAGAGACUGG

3908	1700	UGUAUAAACAGUACCUGAUGC

3909	1701	UGUUAUGAGUAUAAUCCCAGU

3910	1702	UGACUACCCAUAGUUCAUCAC

3911	1703	UCUCAGCUCACCACAACCUCC

3912	1704	UUUAGGUCCAAGUUUCAAACU

3913	1705	AGAGAAAGUCCCAUCUUUGUU

3914	1706	AAAGUUACAGAAGAAUUUCAC

3915	1707	UCCUCAGUGGAGGAGCCGGGG

3916	1708	AUAAAGCUCAUAUUAGACUCC

3917	1709	UAUCAAAUCUUGGUACAAAGU

3918	1710	UUAUUAAAGUUCUCACCUAAA

3919	1711	UCAGUCCUCUUGUUCAGAGCU

3920	1712	UCACCUGGUUUGAGUGCAGGA

3921	1713	CAUCUUCUUCUUCAGACACAG

3922	1714	UUCCCUGACUUUCCCACUGCC

3923	1715	GAAUCGUAUGCUCAAAGUCUG

3924	1716	UCAAGCGAUUCUCCCACCUCA

3925	1717	ACAGUCACUAAUGUACUGAUU

3926	1718	UAACCAACAGAAAGAUUAUAU

3927	1719	GUUCACUCUUAGCAGUCUCAG

3928	1720	AACAUAGUAUGCUUCAAAUUA

3929	1721	AAGCCUUCUAUAACACAAAUU

3930	1722	AUGUUGGGUUAUAUUCAUUUG

3931	1723	AAAGGAGAAGCUCAAGUACAG

3932	1724	CUUCUUCUUCAGACACAGGAG

3933	1725	CUUCCUCUUCAUCUUCUUCUU

3934	1726	AACAGAAAUAGGUGAUACAUA

3935	1727	UCACAGGAAAGGAGAAGCUCA

3936	1728	UAACUAAUGAAUAGGGCUUCC

3937	1729	AUCCUUUGGUUAGAUGGUCUC

3938	1730	UCCCAUUUCUUACAGAGUUGA

3939	1731	AGUGGUAGUAAAGAAGUACCU

3940	1732	AUUUCAGUCCUCUUGUUCAGA

3941	1733	UGGGAUGUAGCCUUCACUGAC

3942	1734	AUACCUUUGCUUAACUGAAUA

3943	1735	CACUCUUAGCAGUCUCAGCCA

3944	1736	CUUCAUUAUCCAGACCGUCAG

3945	1737	AUAUUAAACACAUUCCCAAUG

3946	1738	ACUCUUGUUGCCGAGGCUGGA

3947	1739	GACUCAUUCUCUACUAUCGCU

3948	1740	CUAUGGAAUAAUUGUAACUAG

3949	1741	UCGUAUGCUCAAAGUCUGAAG

3950	1742	AUCUUUCCUGCAGCAGAGUUU

3951	1743	AUGCAAGAGGGACUACUCUCU

3952	1744	CUUCUUCUUCUUCCUCUUCAU

3953	1745	UAAUAAAGCUCAUAUUAGACU

3954	1746	UGAGAAUUAAACUCUAGAAAG

3955	1747	AAGAGGGAGUGUGCAUCUUUG

3956	1748	AUGAUUAAUGUAUCUAUUUCC

3957	1749	UAUUUGCGGGUCCAUAAAGCA

3958	1750	AACUUGUAAGUGUUUAGGUUC

3959	1751	UUGUAAGUGUUUAGGUUCACU

3960	1752	CUCUUGGGUACUAAAUCUGUU

3961	1753	GUUAAGUGACUUGCCUAGCGU

3962	1754	AAGGAGAAGCUCAAGUACAGU

3963	1755	AUACAAUUCUGAUAAACAAUG

3964	1756	AAAGCACACCACACACAAGCA

3965	1757	ACCACUUUAUGGUCACUUCAA

3966	1758	AGUCUCCUAAGAAAGCGUGUG

3967	1759	AAGUGCUGGGAUUACAGGUAU

3968	1760	CAGUCAAUUUAACAGAGCCAU

3969	1761	UAUCCACAUCCAUCUCAAGAC

3970	1762	AGUCAUAUAAGGAAUUCUGUC

3971	1763	ACAAGCCUGAAAGAAAUCUGA

3972	1764	ACAUAUUCCUCUCCACUUUUG

3973	1765	ACUGCUGGUGAAGCAAUGGAU

3974	1766	GUGUCUAUAGUUCCCUUUCUG

3975	1767	UUCUUGGGAUAUGAUUGUAAG

3976	1768	ACUAAGCAGCAUAUCUGAGGU

3977	1769	AAUGCAAGAGGGACUACUCUC

3978	1770	UUCUUUCAUAGGAGAAAUAUU

3979	1771	GACAACAGGAAGCAAUUUCGU

3980	1772	UUUCAGUAUUCUACAUUUAUC

3981	1773	UUUGCAAGGCAACCUAUAAUG

3982	1774	UCAGGCUUAAACGUGAUAUUU

3983	1775	GUAAUCGUGCCCAUUGCUCUG

3984	1776	AGUUAUACAGACAACAGGAAG

3985	1777	ACAGAACCCAAAGUCAGUCAA

3986	1778	GAAACUCUAAAGAAAGUGCUU

3987	1779	UCCUGUACAAAGUACUGGAAU

3988	1780	UCAUAGAAUUUGAGAACAUCU

3989	1781	AUUAUCAAAUCUUGGUACAAA

3990	1782	UUACAAAUAAAUUACAUAAUC

3991	1783	UGAAUAUGGUAUUUGCGGGUC

3992	1784	ACUUAUUAGAAAUAUACAUAA

3993	1785	CAUUUAUAGACAAAUAUCUCA

3994	1786	AAUAUUGUCACUCUUUAUAUC

3995	1787	UGGACUUCCACAUGUUCACAC

3996	1788	ACAUAAAGAAUAAAUACUUGA

3997	1789	AGCUAUCUAAAUAAUUAACAA

3998	1790	ACAAAUAUUUACAAUGACACA

3999	1791	GUUGUUGACUGUUUCUUUGGA

4000	1792	AGGCUGGUCUCGAACUCCUGA

4001	1793	CUGUUGCAAUGUCUAGUGCUG

4002	1794	UUGCUUCAACCACAAUUUAAA

4003	1795	AUUCACAUAAUUCCACCACCC

4004	1796	UUGGGACCAUCCACUAACUCC

4005	1797	UCCUCUUGUUCAGAGCUCAGA

4006	1798	AGACGAAGUUUCACUCUUGUU

4007	1799	CAAUACUUUAGGUCCAAGUUU

4008	1800	UGCUCAGGAGUGAUCUGGGCA

4009	1801	CAAGAGACCAGAUAUCAACUU

4010	1802	CUGUCCUUCAUCCAUACAGGU

4011	1803	UAAUACUUAUUAGAAAUAUAC

4012	1804	UAAUUCCAAGAGACCAGAUAU

4013	1805	UUUCCUUCCCAGUCCACAUGC

4014	1806	UAAUCUGAGGGAGUAGGAAAA

4015	1807	UUGGGUUGCUGUUGAAGGUUC

4016	1808	AGAUAUAUGGUGAAAUAGUAG

4017	1809	AGGAUUUCAGUAUUCUACAUU

4018	1810	CAAUAUUAUAACAAUAUCAAA

4019	1811	GUUUAGGUUCACUCUUAGCAG

4020	1812	UCUAGAACAGCUUGUGGGUUC

4021	1813	UAUAAGGAAUUCUGUCGGACU

4022	1814	AUGGAGGUGAUAUCUCAGUUC

4023	1815	ACUAUGAAGAGGGAGUGUGCA

4024	1816	UGUGGUUGAGUGCUGAAGAAU

4025	1817	AAACACAUUCCCAAUGCAUGU

4026	1818	UAUCUUUGGUUCCCAACAAAU

4027	1819	AAGCCUAUGGAAUAAUUGUAA

4028	1820	AAUGACACACACACGAGAUCA

4029	1821	CUUCCAUCUUUCCUGCAGCAG

4030	1822	AUAAAUACUUGAGUUAAAUCU

4031	1823	UCCUUCUUCCUAGGCUAGUAU

4032	1824	UCAUUAUCCAGACCGUCAGAC

4033	1825	UGGGAUAGCAUUUGCCUGAUG

4034	1826	UCCUUUGCAGCGAUAAUCAGA

4035	1827	UUUAUAUCUCUAUGGAUCACC

4036	1828	GAAGUUUCACUCUUGUUGCCG

4037	1829	CAUCUUUGUUUAAAUGUGGUU

4038	1830	ACACUAUGAAGAGGGAGUGUG

4039	1831	AUGCACAAUCCAUAUUUCAAU

4040	1832	CUGUUCUUAAUUGCUUCCUUU

4041	1833	CUUUGCUCAGGAGUGAUCUGG

4042	1834	UACAGGAUUCUGUGAAGAUCU

4043	1835	AAAUACCUUUAAUCCAAAGUU

4044	1836	AGCUCAUAUUAGACUCCGGGG

4045	1837	AACUGCAAGUAGCUUAGAUAA

4046	1838	AACAACUUUCUGUAAUUUACA

4047	1839	UAACAACAUUAACGUUCUUUC

4048	1840	CAUGGUGACUGAUUUGAGGGG

4049	1841	UUUGCGGGUCCAUAAAGCACA

4050	1842	AGUGCUGUAUAAACAGUACCU

4051	1843	UGAAGGAGGUUUGAAUGCAAG

4052	1844	UUGCUUCCUUUGCAGCGAUAA

4053	1845	UCUCUACUAUCGCUGUUGAUU

4054	1846	AUAGGUGAUACAUAGGAAAAA

4055	1847	AUUCAACCUGAGAGUCUGUUA

4056	1848	AUUCUGUCGGACUGACAUUUC

4057	1849	GUAGACAUCACUACCCUGUGA

4058	1850	AGAUGGUCUCCCUUGCUCUUU

4059	1851	UCCCACCAUAGUGCUUCGUUU

4060	1852	UGUACCAAAUGUGAAUCCUUC

4061	1853	UGGUAUUAUGGGAUAGCAUUU

4062	1854	AAUAUUAGGGUUCUUAUUUUC

4063	1855	UCAGGCUGGAGAGAGGCUUGG

4064	1856	GUAGCUACAGGAUUCUGUGAA

4065	1857	UCUCCUAAGAAAGCGUGUGCC

4066	1858	CACUCUUUAUAUCUCUAUGGA

4067	1859	ACAACCUCCGCCUCCUGGGUU

4068	1860	UGACCUCCCAUUUCUUACAGA

4069	1861	ACAACGCACUGGAUCCUUGCU

4070	1862	UAUGGUAUUUGCGGGUCCAUA

4071	1863	CUUGGUGCGAUAACUGGUGGU

4072	1864	CUCUUCAUUAUCCAGACCGUC

4073	1865	CUCCUCAUCUGUCAUCUUGGA

4074	1866	UCUUUCCUGCAGCAGAGUUUU

4075	1867	UAUCAUCAAUAAUGAAUAUGG

4076	1868	ACACUAGCAACAUCAAAGAUU

4077	1869	CACACAGUACUUGCUCUGGUA

4078	1870	AUUCCUAACUCAGGACAUUUU

4079	1871	UCCUGACCUCAGGUGAUCCGC

4080	1872	UCAACCACAGAACGAGUAUAG

4081	1873	ACAAACACAACACUAUGAAGA

4082	1874	AGAUUCAGUUAGACAUUGUUU

4083	1875	UCCACUGGAGAGAAUUUCAAG

4084	1876	ACUAACUCCCAGUUUACCCUC

4085	1877	CACACAGGUGUGCACAUGGAG

4086	1878	CCAGACUUUACAUACAGACUG

4087	1879	AUCACCUGGUUUGAGUGCAGG

4088	1880	AAAGACCAAGAGAUUCAACCG

4089	1881	CUGCAGACAGCUGCUAUCUGU

4090	1882	AUUUCCUCCUGGUAUGCCUAU

4091	1883	AUGUUUCAUAAGCACAAGAGA

4092	1884	UUCCCAAUGCAUGUUGGGUUA

4093	1885	ACAUGGACACACAAAUAUUUA

4094	1886	GAACACACAUAUUCCUCUCCA

4095	1887	UCUUUGAGCUGAGAAAUAUCA

4096	1888	AGAAGAAUUUCACUACACAUG

4097	1889	UAUCCUGUUGGACAAGAAAAU

4098	1890	AGGAAGAGAGAUCUCUGGGCG

4099	1891	CAGCUGACAGUCUCUCAGGAU

4100	1892	CCUAAGGAUCAUCUAGUCCAA

4101	1893	UGUUAAUAUGCUGAACUGAAA

4102	1894	UCACCCACCAAGUAGCUAUCU

4103	1895	UCCCAGUAGACAUCACUACCC

4104	1896	AUAAGAAGUUUCUAUUCAUUU

4105	1897	ACAGAACGAGUAUAGAUUGAU

4106	1898	AUGGGCUCUGCUAUCUUGUGC

4107	1899	CUAAGGAUCAUCUAGUCCAAU

4108	1900	UAUUUCCAAGUUCCCAUUUAU

4109	1901	AUCCAGACCGUCAGACAUUUU

4110	1902	CAUCCAUCUCAAGACAGCGAU

4111	1903	AUUUGCAUCCCAGGAUUUCAU

4112	1904	AUCAAUAAUGAAUAUGGUAUU

4113	1905	UUCAUUUGAAAGGUAAAGAAC

4114	1906	AUCAGAGGAGUCAGGCUGGAG

4115	1907	AUGGUCUCCCUUGCUCUUUAA

4116	1908	UGGUGCGAUAACUGGUGGUGG

4117	1909	ACAAUGCUUCUUAGCUUCUCU

4118	1910	AAGCAUGAACACACCAUAUUC

4119	1911	UAAGGCCUCUCUCUCUCAUUA

4120	1912	UGCAAGGCAACCUAUAAUGCC

4121	1913	UUCAUUGAAUUUCCCGGCACU

4122	1914	AGGCUUGCAGUCUUAGCGGCU

4123	1915	AGGAAUAUAAUUAUUUACACG

4124	1916	AUUCAACCACAGAACGAGUAU

4125	1917	ACAGCUUGUGGGUUCUUCUUC

4126	1918	CUGCUAUCUGUCCUUCAUCCA

4127	1919	CUGAACAUAAACACGUACACU

4128	1920	AAUUCCUUCUUGGGUUGCUGU

4129	1921	UGAACACACCAUAUUCCGAAA

4130	1922	AAGUCAUAACUUCUAUUGAAA

4131	1923	AUCAACAUUGAAAGAUGUGCC

4132	1924	AUCAUAGAAUUUGAGAACAUC

4133	1925	GAACAUAAACACGUACACUAU

4134	1926	UACUGCUGGUAUUAUGGGAUA

4135	1927	UGGUGAGGUGUAAGGCUUGCA

4136	1928	GAAUAUAAUUAUUUACACGAU

4137	1929	AUAGCAGGCUGAAUUUGCAAG

4138	1930	GUCGGACUGACAUUUCUUGGG

4139	1931	CUUGAGAAUUAAACUCUAGAA

4140	1932	AGAUGGUGAGGUGUAAGGCUU

4141	1933	AUAACAUAAAGAAUAAAUACU

4142	1934	CACAUGGAGGUGAUAUCUCAG

4143	1935	CCAUAGUUCAUCACCCACCAA

4144	1936	AAGAUGUGGAUAUAUGGAUGG

4145	1937	UUAGAAAUAAACCCAUUGAGC

4146	1938	CAGUCUCUCAGGAUUCUGGAG

4147	1939	CAUAGUGCUUCGUUUACUUUG

4148	1940	ACACUAUAUAGUUUGCUGAAA

4149	1941	UUUCAGGUAUUAAGGAGAUUA

4150	1942	AAUGAGAUACAAUUCUGAUAA

4151	1943	GUGACUUCUCUAGGUAUAGGG

4152	1944	CUGGUCUCGAACUCCUGACCU

4153	1945	AGUUCUGUUUAGAUUCUUUUA

4154	1946	UGCACAUGGAGGUGAUAUCUC

4155	1947	UGCUUCUUAGCUUCUCUAAGA

4156	1948	UUCAGGUAUUAAGGAGAUUAA

4157	1949	UCUCCCUAGCUUUAACUUAUA

4158	1950	AUUCUACAUUUAUCUGGUUUU

4159	1951	GUCCACAUGCAAAUACACGUU

4160	1952	AACAUUUCUCAAUGCUAAUAG

4161	1953	AUCCACAUCCAUCUCAAGACA

4162	1954	UGAUUUCCUCUUGGGUACUAA

4163	1955	AUAAUCCCAGUAGACAUCACU

4164	1956	AUAUGUUUCAUAAGCACAAGA

4165	1957	AGUGUUUAGGUUCACUCUUAG

4166	1958	UAUUAAACACAUUCCCAAUGC

4167	1959	GAUUAUGACAACGCACUGGAU

4168	1960	UCUGGACAUCUAAUGACAAUG

4169	1961	CUAUAACACAAAUUGUUAGUU

4170	1962	UGGAGCUCUGGAGUUCCAUUA

4171	1963	UGAACUCACCUAGCAGGAUGU

4172	1964	AUGGACUUCCACAUGUUCACA

4173	1965	UGCCUACAGUGAUCUGAAGGG

4174	1966	UGUACAUAAGUUCUGUUUAGA

4175	1967	AAAUAUUUACAAUGACACACA

4176	1968	AGCAAUAUUAUAACAAUAUCA

4177	1969	CACUACAUCUGACUCAUUCUC

4178	1970	UUCAAAGUGAAUGCACAAAAU

4179	1971	UCUAUUGAAAUUAGUGGGACU

4180	1972	ACAUCUCCCUAGCUUUAACUU

4181	1973	AUUAAUUUAGGUAUCAUUAUC

4182	1974	CUCUCUCUCUCAUUAGAGCAG

4183	1975	UCAGUUCCCGCAUUUGCAGAU

4184	1976	UGCAAUGUCUAGUGCUGUAUA

4185	1977	CUUUGAGCUGAGAAAUAUCAU

4186	1978	AAUAAAUAAUCUCUACUGUGC

4187	1979	AGUAGCUGGGAUUACAGGCGC

4188	1980	AAUGUCCAACAAGGAUUUCAG

4189	1981	AUUUCUUUGGUGAGUUAGAAG

4190	1982	UCUUUAUAUCUCUAUGGAUCA

4191	1983	UAUUUGCAAUACUUUAGGUCC

4192	1984	AGAUACAAUGCCCUGAGUGGA

4193	1985	AUUUGCGGGUCCAUAAAGCAC

4194	1986	CAAAUAAAUUACAUAAUCUGA

4195	1987	UUGCAAGGCAACCUAUAAUGC

4196	1988	CUGUGAAGAUCUUAUCAUCAA

4197	1989	UCCCUUUCUGCUGUUUAUUUA

4198	1990	AGAGACUGGGAGAUACUUGCA

4199	1991	UGGGCUGCUAUGUAUCCAUGU

4200	1992	UCAUGUAUUUCUGGUUGUUGA

4201	1993	AAGUGACUUGCCUAGCGUCAC

4202	1994	GAAAGCAUAAGAGAGAAGCCA

4203	1995	GAAAUUAGUGGGACUUGCCCU

4204	1996	GAGAGGUUAAGUGACUUGCCU

4205	1997	CUAAUAGCAUGUAAUUACUUU

4206	1998	UCUUGGGAUAUGAUUGUAAGU

4207	1999	UGUCUAUAGUUCCCUUUCUGC

4208	2000	UCAAACUGUCAGUUUACAAAU

4209	2001	AUAAUUCCAAGAGACCAGAUA

4210	2002	AGGUUCACUCUUAGCAGUCUC

4211	2003	CUACCCAUAGUUCAUCACCCA

4212	2004	CUUGGGUUGCUGUUGAAGGUU

4213	2005	GACCAGAUAUCAACUUUCGGA

4214	2006	AAUAAUCUCUACUGUGCUUCU

4215	2007	GUUACAACUAAUUUCACAGCU

4216	2008	GUCACUUCAACAUUGCUGCCC

4217	2009	CUCAUUCUCUACUAUCGCUGU

4218	2010	AGUGACAUCUCCCUAGCUUUA

4219	2011	UUUGGUGAGUUAGAAGGAAGU

4220	2012	CUUUAUUUAGAUAUACAGUUU

4221	2013	UACUGUGCUUCUCACCCUUCC

4222	2014	UAAGGAUCAUCUAGUCCAAUA

4223	2015	CAUUCUCUACUAUCGCUGUUG

4224	2016	UGCAGACAGCUGCUAUCUGUC

4225	2017	CAUCACUACCCUGUGAUCUGG

4226	2018	CUCUUUAUUUGGUACUGCUGG

4227	2019	ACAUUCCCAAUGCAUGUUGGG

4228	2020	UGCUGGGAUUACAGGUAUGAG

4229	2021	ACAUGGUUUACAGAUAACACA

4230	2022	UUAAUAUGCUGAACUGAAAGC

4231	2023	GUACUAAAUCUGUUGAACAUG

4232	2024	AAGGAAUUCUGUCGGACUGAC

4233	2025	ACAGCUGCUAUCUGUCCUUCA

4234	2026	GUCAUCAGAAAUGCUAUCUUU

4235	2027	CUGGUUUACUCAAUUAUCUUU

4236	2028	AAAUUAAUUUGUCAACAUUUC

4237	2029	ACAUAGUAUGCUUCAAAUUAA

4238	2030	CAUUGUUAAUAUGCUGAACUG

4239	2031	AUGGAGGCUCAGAUGCUGUUU

4240	2032	CAAAGUGGUAGUAAAGAAGUA

4241	2033	UUUCCUCCUGGUAUGCCUAUU

4242	2034	AACUCUAGAAAGCCCAGCACU

4243	2035	UCACCACAACCUCCGCCUCCU

4244	2036	AUUUAACUGCAACAUAAGAGA

4245	2037	UUAUUUCCUUCCCAGUCCACA

4246	2038	GUGAUCUGAAGGGUCACUGCU

4247	2039	UCACUAUAGCAGGCUGAAUUU

4248	2040	AUGUAUUUCUGGUUGUUGACU

4249	2041	AAUACUUUAGGUCCAAGUUUC

4250	2042	CUAAGCAUGAACACACCAUAU

4251	2043	AUGGAUCACCUGGUUUGAGUG

4252	2044	UUUGUUUAAUGAUUUCAAAGU

4253	2045	AUCUCUACUGUGCUUCUCACC

4254	2046	AAGAUCUCCUCAUCUGUCAUC

4255	2047	CAAACAACCUAUAAAUAGGCA

4256	2048	AUUAUGACAACGCACUGGAUC

4257	2049	ACAUGUAAGGGAUGCUAACUA

4258	2050	GAAAUAUUCCAUUAUUUCCAA

4259	2051	AUUCUUUCAUAGGAGAAAUAU

4260	2052	CCAGUCUUUGUCCAUAUGCAU

4261	2053	UCUGACUCAUUCUCUACUAUC

4262	2054	AACAUCAAAGAUUUGGAUAGA

4263	2055	CACAAUGCUUCUUAGCUUCUC

4264	2056	CAGAUAUCAACUUUCGGACCA

4265	2057	AUAUCUGCAACAGAUGUUAUC

4266	2058	AGGCCUAUGUAACUGAUCUCU

4267	2059	UCCUUUGGUUAGAUGGUCUCC

4268	2060	AAUCCCAGGCCCAUCAAACUG

4269	2061	UCCAAAGUUACAGAAGAAUUU

4270	2062	AGAGAAUAAACUGUUAACAAU

4271	2063	UAGUUCCCUUUCUGCUGUUUA

4272	2064	AUGAUCUCAGCUCACCACAAC

4273	2065	UGAGAAAUAUCAUUUAUAGAC

4274	2066	ACUUUAUGGUCACUUCAACAU

4275	2067	AUGUAUCCAUGUGCACUUUUA

4276	2068	AUUGCUUCCUUUGCAGCGAUA

4277	2069	AGUAUUUCUGUAUUGAGAAUG

4278	2070	CAUAAAGCACACCACACACAA

4279	2071	UGGUCACUUCAACAUUGCUGC

4280	2072	CUUGUGGGUUCUUCUUCUGUU

4281	2073	AUCUCCCUAGCUUUAACUUAU

4282	2074	UUGCCGAGGCUGGAGUGCAAU

4283	2075	AGUAUAACAUAGUAUGCUUCA

4284	2076	AGGGACUACUCUCUAACUUAA

4285	2077	AGAACGAGUAUAGAUUGAUUU

4286	2078	AAUAUAAUUAUUUACACGAUC

4287	2079	UUGGUUCCCAACAAAUUAAUU

4288	2080	AAGGCCUCUCUCUCUCAUUAG

4289	2081	GAUAGAUGUAAGGAUCAGGUG

4290	2082	AUCCAUCUCAAGACAGCGAUU

4291	2083	AUCUGAAUAACAUAAAGAAUA

4292	2084	UGUUUAAUAUUAAACACAUUC

4293	2085	CUUCUAUAACACAAAUUGUUA

4294	2086	AAUAACAUAAAGAAUAAAUAC

4295	2087	CAAUGCAUUAGUAGCUACAGG

4296	2088	AAGCCUGAAAGAAAUCUGAAU

4297	2089	UGAAGGGUCACUGCUCCAAGG

4298	2090	UAUAGACAAAUAUCUCAAACU

4299	2091	GUUGAGUGCUGAAGAAUCCCG

4300	2092	ACCAAGAGAUUCAACCGGGGA

4301	2093	CUUUAUAUCUCUAUGGAUCAC

4302	2094	AUAAAUACCUUUAAUCCAAAG

4303	2095	AAAGUGGUAGUAAAGAAGUAC

4304	2096	AAGGAAUAUAAUUAUUUACAC

4305	2097	AGGCUUACAAAUAAAUUACAU

4306	2098	UCUCAACAUGUAAGGGAUGCU

4307	2099	GAUUAAUGUAUCUAUUUCCUC

4308	2100	ACCUGAACUCACCUAGCAGGA

4309	2101	AGUAAAUGCUACAAGUUGUAU

4310	2102	AGUUGUAUAGAAUACUCGUAC

4311	2103	UCAUAAGCACAAGAGAGGAUU

4312	2104	UGCUAUGUAUCCAUGUGCACU

4313	2105	CAGAAGAAUUUCACUACACAU

4314	2106	AUAUCUCUGCCCUGCAUGCUC

4315	2107	ACCUUUAAUCCAAAGUUACAG

4316	2108	AUCCUCAUGGGAUUAUGACAA

4317	2109	AAUUUGUAUCAUAAGUAAAUG

4318	2110	AGUCACUAAUGUACUGAUUUU

4319	2111	UCAAAUUAAUAUUACCGUUUC

4320	2112	GAUUUGGAUAGACUCACCUGU

4321	2113	UUGUUGCCGAGGCUGGAGUGC

4322	2114	CUACACAGACACUCCGCAGAU

4323	2115	AAAUCCAAAGCUUGCAGGCAC

4324	2116	AUAUCUCAGUUCCCGCAUUUG

4325	2117	AGUCUUUGUCCAUAUGCAUUU

4326	2118	AUUAAUUCCUUCUUGGGUUGC

4327	2119	UGUGGAUAUAUGGAUGGUUAG

4328	2120	UUGUUUAAAUGUGGUUUCUCC

4329	2121	AGACACUCCGCAGAUAUUUUU

4330	2122	UGUGAAUCCUUCAGCAUCACU

4331	2123	CAUCUAGUCCAAUACACUUAU

4332	2124	CUCGAUUGUACCAAAUGUGAA

4333	2125	AUCUUUGUUUACUUAAUGUCC

4334	2126	UAAUCCCUGUUUAUGUUAUUU

4335	2127	AUUACCCAACAUGGUGACUGA

4336	2128	CAUAAUCUGAGGGAGUAGGAA

4337	2129	AUAAACCCAUUGAGCAAAGGA

4338	2130	AGAUGUGGAUAUAUGGAUGGU

4339	2131	AGCUUAGAUAAAGACCAAGAG

4340	2132	UGGAGAGAAUUUCAAGACAUU

4341	2133	ACACAUUCCCAAUGCAUGUUG

4342	2134	CAAGUUCCCAUUUAUUUCCUU

4343	2135	CAACACUCACAAUGCUUCUUA

4344	2136	AUGAAUACAAAUUUAUAAAAG

4345	2137	UGAAUAUUAACUGCAAGUAGC

4346	2138	AGAGGGUGGUGUGACCUCUUU

4347	2139	UGCAGCGAUAAUCAGAGGAGU

4348	2140	AUAUUCAUUUGGUCACUUAAA

4349	2141	UGCAAGUUCAACCCAAUUAAG

4350	2142	GAAUCAACAUUGAAAGAUGUG

4351	2143	UAAAUAGAUAUAUGGUGAAAU

4352	2144	AGAUGUUAUGAGUAUAAUCCC

4353	2145	GUAGCUUAGAUAAAGACCAAG

4354	2146	AGUCAGGCUGGAGAGAGGCUU

4355	2147	AUCUUAUCAUCAAUAAUGAAU

4356	2148	CAACAUGGUGACUGAUUUGAG

4357	2149	UGGGAAGUGGUUUGGAGCUGU

4358	2150	AAGAUCUUAUCAUCAAUAAUG

4359	2151	CAUUGCUCUGGAAUUCCAGUG

4360	2152	AGAAAUCUGAAUAACAUAAAG

4361	2153	ACAUUAACGUUCUUUCCUUUU

4362	2154	AGGGAAAGAGAAUAAACUGUU

4363	2155	CAGGAUUCUGGAGCUCUGGAG

4364	2156	CAAAUGCUGAAUUUCAGUCCU

4365	2157	CAACACUAUGAAGAGGGAGUG

4366	2158	AGGGCACACUAGCAACAUCAA

4367	2159	GAAGUCAUUACCCAACAUGGU

4368	2160	CAACUUUCUGUAAUUUACAAA

4369	2161	CAUCUCCCUAGCUUUAACUUA

4370	2162	GAAAUAGGUGAUACAUAGGAA

4371	2163	AACAACCUAUAAAUAGGCAGA

4372	2164	UGUGACCACAUCAGUCAGAGA

4373	2165	UACAAUGCCCUGAGUGGAUUU

4374	2166	AGUCCACAUGCAAAUACACGU

4375	2167	AGUCUUACUCAUGAGGGAGAU

4376	2168	UAGCUUAGAUAAAGACCAAGA

4377	2169	AUUUGCAAGGCAACCUAUAAU

4378	2170	AUUUGUCAACAUUUCUCAAUG

4379	2171	GUAUGCUCUGGUCUUGGUGCG

4380	2172	CACUAUAGCAGGCUGAAUUUG

4381	2173	CAGAUUCAGUUAGACAUUGUU

4382	2174	UAUGGAUGGUUAGAUGGAUGG

4383	2175	CUUAGCUUCUCUAAGAUCUCC

4384	2176	UCCUCCUGGGAAGAUAGAGCG

4385	2177	AGGUCAGAAGGAUGGAACCAU

4386	2178	CAACAGAUGUUAUCAAGGGGG

4387	2179	CAACUACUGCAAACAACCUAU

4388	2180	UCACCUUCCACCAUUUCAAUU

4389	2181	AAUGGAGGCUCAGAUGCUGUU

4390	2182	CUAGUAUUUAUCCCACUACAU

4391	2183	CAUGUUCACACAGUACUUGCU

4392	2184	GUACACACAGGUGUGCACAUG

4393	2185	ACACGAGAUCAGCAAGAACGA

4394	2186	ACUUCAACAUUGCUGCCCUGU

4395	2187	GUUCCCACCAUAGUGCUUCGU

4396	2188	AAUUCUGAUAAACAAUGAAAA

4397	2189	AACAGGCAGAGACAGUCCUAC

4398	2190	CUGUGCUUCUCACCCUUCCCU

4399	2191	AAUUACAUAAUCUGAGGGAGU

4400	2192	AGCGAUAAUCAGAGGAGUCAG

4401	2193	UGAUUGGGAUGUAGCCUUCAC

4402	2194	UGGGACUUGCCCUAUUGGUUA

4403	2195	UGGAUCACCUGGUUUGAGUGC

4404	2196	UUGGUCAGGCUGGUCUCGAAC

4405	2197	UCCUACAUAUUUGUUUAAUGA

4406	2198	ACCACAUCAGUCAGAGAGCCA

4407	2199	AGAGAAACAACUUUCUGUAAU

4408	2200	UCCUUCUUGGGUUGCUGUUGA

4409	2201	UACAGACAACAGGAAGCAAUU

4410	2202	UGGAAUCAACAUUGAAAGAUG

4411	2203	AUAAUCUGAGGGAGUAGGAAA

4412	2204	AGUGGUUUGGAGCUGUGGUUG

4413	2205	UGCCUAGCGUCACAUAGCAAU

4414	2206	AUCCCGAGAAGAAUAUUGUCA

4415	2207	UAUUAAAGUUCUCACCUAAAA

4416	2208	AAAGCAAUAUUAUAACAAUAU

4417	2209	AUUCCCAAUGCAUGUUGGGUU

4418	2210	CUAGCUUUAACUUAUAGAUAA

4419	2211	CAUCCAUACAGGUCUCUGUGA

4420	2212	UGUACUCGAAGGAUGGGCUGC

4421	2213	UCCAAAGCUUGCAGGCACUCU

4422	2214	AGGUGGUUAAACUCAAACAUU

4423	2215	AUUUGUUUAAUGAUUUCAAAG

4424	2216	UUGGUACAAAGUGGUAGUAAA

4425	2217	UAUGAAGAGGGAGUGUGCAUC

4426	2218	CAAAUAUUUACAAUGACACAC

4427	2219	CUGAAGGAAGAGAGAUCUCUG

4428	2220	UGCUCUGGAAUUCCAGUGAAU

4429	2221	AGAGAGGCCUAUGUAACUGAU

4430	2222	GAAUACAGCUGACAGUCUCUC

4431	2223	AAGUUUCAAACUGCAAUAUUU

4432	2224	CUGACCUCAGGUGAUCCGCCU

4433	2225	ACUGGGAACAGUCAACAGAAA

4434	2226	GUUAUGAGUAUAAUCCCAGUA

4435	2227	UUGUUUACUUAAUGUCCAACA

4436	2228	CUAUAUAGUUUGCUGAAACUC

4437	2229	AUUCAUUUGGUCACUUAAAGG

4438	2230	CUUAAACGUGAUAUUUGCCAU

4439	2231	CACCACAACCUCCGCCUCCUG

4440	2232	AAUGUGGUUUCUCCUAUGAGG

4441	2233	UGAGGGAGAUGGUGAGGUGUA

4442	2234	UGGGUUAUAUUCAUUUGGUCA

4443	2235	AACGCACUGGAUCCUUGCUAA

4444	2236	UUACUUUGCUCAGGAGUGAUC

4445	2237	CUCUGCAACUUGUAAGUGUUU

4446	2238	CUCUAAGAUCUCCUCAUCUGU

4447	2239	AGGAUGUCACAGUUUCAGUUU

4448	2240	UCUCUACUGUGCUUCUCACCC

4449	2241	AGAAUUUCAAGACAUUUAUGA

4450	2242	UCACUGUGGGAGUUGUCAUCA

4451	2243	AAUACUUAUUAGAAAUAUACA

4452	2244	AGUCCUCUUGUUCAGAGCUCA

4453	2245	CAAACACAACACUAUGAAGAG

4454	2246	CAGCUUCUAAAGGAGACUCCG

4455	2247	UGGGACCAUCCACUAACUCCC

4456	2248	AUCAAAGAUUUGGAUAGACUC

4457	2249	UGGGAUUACAGGCGCCCGCCA

4458	2250	CUAACCAACAGAAAGAUUAUA

4459	2251	AAGUAGCUAUCUAAAUAAUUA

4460	2252	CUUUAUGGUCACUUCAACAUU

4461	2253	AGGUAUUAAGGAGAUUAACAA

4462	2254	AAAUUAAGAAGCCUUCUAUAA

4463	2255	ACAGUCAUGCACAAUCCAUAU

4464	2256	UCAGGGCACACUAGCAACAUC

4465	2257	AGACUCAGGCUUAAACGUGAU

4466	2258	GGACCAUCCACUAACUCCCAG

4467	2259	CUGAAUAACAUAAAGAAUAAA

4468	2260	UGGGUUGCUGUUGAAGGUUCA

4469	2261	UGCUACAAGUUGUAUAGAAUA

4470	2262	CUAUAGUUCCCUUUCUGCUGU

4471	2263	GUGUGCAUCUUUGAGAAACCU

4472	2264	CUAGGUAUAGGGUCUGCUUUU

4473	2265	UCUAUUUCCUCCUGGUAUGCC

4474	2266	AAUAUACAUAACUCUCCAAUA

4475	2267	GUAAAGCUCAUGUAUUUCUGG

4476	2268	UUCCCUUUCUGCUGUUUAUUU

4477	2269	CACAUGCAAAUACACGUUCAG

4478	2270	UCGAGUCACCACCUCAGGUGC

4479	2271	GAGGUGAUAUCUCAGUUCCCG

4480	2272	GUCUUGGUGCGAUAACUGGUG

4481	2273	GUUUACUAUAUCACCUUUCUC

4482	2274	CUCUCUGCAACUUGUAAGUGU

4483	2275	ACUUUCGGACCAUAAGCUUUU

4484	2276	AAUAUUGAUUGGGAUGUAGCC

4485	2277	GUUUGAGUGCAGGAAAUCCAA

4486	2278	CAGAAUUUCAUUAAUAAUUAA

4487	2279	AGUACUUGCUCUGGUAUUUUU

4488	2280	UUUCCAAGUUCCCAUUUAUUU

4489	2281	AAACAGCUUCUUUCUAAUACU

4490	2282	UGCUAACAACAUUAACGUUCU

4491	2283	AGGUCCAAGUUUCAAACUGCA

4492	2284	UUCAGUCCUCUUGUUCAGAGC

4493	2285	UUCUCAACAUGUAAGGGAUGC

4494	2286	GAAGGAAGAGAGAUCUCUGGG

4495	2287	UGUAGAUGUUAUGAGUAUAAU

4496	2288	AGGCACUCUCUGCAGACAGCU

4497	2289	ACAUCUGACUCAUUCUCUACU

4498	2290	CCUCUUUAUUUGGUACUGCUG

4499	2291	UCAAGCCUCUCCCAACUUUUA

4500	2292	UCAUGAGGGAGAUGGUGAGGU

4501	2293	ACAUUGAAAGAUGUGCCCUCG

4502	2294	UCUGCCCUGCAUGCUCUGCGC

4503	2295	CUCUGGGCGCUCUUUCUCCUU

4504	2296	CACCACCCUAACACAACUGAU

4505	2297	ACAUAAUCUGAGGGAGUAGGA

4506	2298	CAAUAUCUGCAACAGAUGUUA

4507	2299	UCAAUGCUAAUAGCAUGUAAU

4508	2300	CAUGGUUUACAGAUAACACAU

4509	2301	UGUAAGUGUUUAGGUUCACUC

4510	2302	AUAUUAUAACAAUAUCAAAUA

4511	2303	UCUAUUCAUUUGAAAGGUAAA

4512	2304	AUGGGCUGCUAUGUAUCCAUG

4513	2305	GAUAUAUUAUUAUCAAAUCUU

4514	2306	CUCAGGAUUCUGGAGCUCUGG

4515	2307	AUGUAAGGGAUGCUAACUAAU

4516	2308	AAACUGUCAGUUUACAAAUGC

4517	2309	GAAUUCUGUCGGACUGACAUU

4518	2310	AUAGUGCUUCGUUUACUUUGC

4519	2311	AUCUCAGUUCCCGCAUUUGCA

4520	2312	UAUUGAGAAUGACCAAUAAAA

4521	2313	UGGUCACUUAAAGGAGUGUGG

4522	2314	GAGUGCUGAAGAAUCCCGGUU

4523	2315	UACCUUUAAUCCAAAGUUACA

4524	2316	ACAUCUAAUGACAAUGCAAGU

4525	2317	CCACACACAAGCACACACAUU

4526	2318	CAGGUGGUUAAACUCAAACAU

4527	2319	UCCACAUGUUCACACAGUACU

4528	2320	UUAUAACAAUAUCAAAUAAAA

4529	2321	UCUUGCAAGUUCAACCCAAUU

4530	2322	CAGUAAAUGCUACAAGUUGUA

4531	2323	UGCAUAUGUUUCAUAAGCACA

4532	2324	CAGCUCACCACAACCUCCGCC

4533	2325	ACUUCCACAUGUUCACACAGU

4534	2326	GUUUACUUAAUGUCCAACAAG

4535	2327	UAAAUACCUUUAAUCCAAAGU

4536	2328	CUAGCAACAUCAAAGAUUUGG

4537	2329	ACUCUAGAAAGCCCAGCACUA

4538	2330	AUACCUUUAAUCCAAAGUUAC

4539	2331	AGAAAGUCCCAUCUUUGUUUA

4540	2332	CAAGGCAACCUAUAAUGCCAU

4541	2333	CCUCAUUAGAAAUAAACCCAU

4542	2334	AGGAAAUCCAAAGCUUGCAGG

4543	2335	UCUUCAUUAUCCAGACCGUCA

4544	2336	ACAUAAACACGUACACUAUAU

4545	2337	GUGUUUGGAGUUCUAAUAGUG

4546	2338	ACAGACACUCCGCAGAUAUUU

4547	2339	CUAAAUAAUUAACAAUAUUAG

4548	2340	CUGUUGAUUUCCUCUUGGGUA

4549	2341	AGCUCUGGAGUUCCAUUAGUG

4550	2342	GUGAUAUUAUAGAAUCUCUCA

4551	2343	ACCUAGCAGGAUGUCACAGUU

4552	2344	UUUCACCGUUUGAGCUUUAUU

4553	2345	UGUCACAGUUUCAGUUUCAGU

4554	2346	CCUUGCUAACAACAUUAACGU

4555	2347	AGCUUUAUUUAGAUAUACAGU

4556	2348	UAUUUGCAUCCCAGGAUUUCA

4557	2349	AUUGAAAUUAGUGGGACUUGC

4558	2350	UGUAUGCUCUGGUCUUGGUGC

4559	2351	UCACCCUUCCCUGACUUUCCC

4560	2352	GUGAUAUCUCAGUUCCCGCAU

4561	2353	CAACAGGAAGCAAUUUCGUGU

4562	2354	CUACCUGAAUGAUAUACAGUA

4563	2355	CUCUUCAUCUUCUUCUUCAGA

4564	2356	CACUGUGGGAGUUGUCAUCAG

4565	2357	AAGGAUGGAACCAUACCAUCA

4566	2358	UGUUCCCAGUCUUUGUCCAUA

4567	2359	AUUACAGGCCCAGAUUCGUUU

4568	2360	GUUUGGAGUAAUCGUGCCCAU

4569	2361	UGAAAGAUGUGCCCUCGUUAU

4570	2362	AAUGUGAAUCCUUCAGCAUCA

4571	2363	CUCUAGGUAUAGGGUCUGCUU

4572	2364	GUUUCUAUUCAUUUGAAAGGU

4573	2365	ACUCAUGAGGGAGAUGGUGAG

4574	2366	CUCAGCUCACCACAACCUCCG

4575	2367	ACACCAUAUUCCGAAACAGAA

4576	2368	AAUUUCAUUAAUAAUUAAUUC

4577	2369	ACACCACACACAAGCACACAC

4578	2370	AGAGGGAGUGUGCAUCUUUGA

4579	2371	AAACGUUAUAAAUUGUCAAAA

4580	2372	AGUCAUGCACAAUCCAUAUUU

4581	2373	GUAUUUCUGGUUGUUGACUGU

4582	2374	UAUCUCAGUUCCCGCAUUUGC

4583	2375	AGUGCUGAAGAAUCCCGGUUG

4584	2376	GAGUUGUCAUCAGAAAUGCUA

4585	2377	CACUACUUCACAGGAAAGGAG

4586	2378	CUCUAUGUUGGUCAGGCUGGU

4587	2379	UCGAAGGAUGGGCUGCUAUGU

4588	2380	AGAAUUAAACUCUAGAAAGCC

4589	2381	AUCACUGUGGGAGUUGUCAUC

4590	2382	CUAUAUCACCUUUCUCUAGAU

4591	2383	AAAUGUGAAUCCUUCAGCAUC

4592	2384	ACACACAAAUAUUUACAAUGA

4593	2385	ACUCGAUUGUACCAAAUGUGA

4594	2386	AAGAAUCCUACCUGAAUGAUA

4595	2387	CAUAAAGAAUAAAUACUUGAG

4596	2388	AUCAGAUACAAUGCCCUGAGU

4597	2389	ACAUCACUACCCUGUGAUCUG

4598	2390	UGCAAACAACCUAUAAAUAGG

4599	2391	CAUAGUUGUAAUCCCUGUUUA

4600	2392	ACAGUCCUACAUAUUUGUUUA

4601	2393	GGGAUUAUGACAACGCACUGG

4602	2394	UCCUUGCUAACAACAUUAACG

4603	2395	ACGAAGUCAUUACCCAACAUG

4604	2396	UACUCAUGAGGGAGAUGGUGA

4605	2397	AGAACUAAGCAUGAACACACC

4606	2398	AAUCAACAUUGAAAGAUGUGC

4607	2399	UCUUUGUUUAAAUGUGGUUUC

4608	2400	CUUUGGUUAGAUGGUCUCCCU

4609	2401	AGAUCAGCAAGAACGAAGUCA

4610	2402	GUUUGCUGAAACUCUAAAGAA

4611	2403	AGAAGCCUUCUAUAACACAAA

4612	2404	CUUUGCUUAACUGAAUAUUAA

4613	2405	AUAUCAACUUUCGGACCAUAA

4614	2406	ACACACAUAUUCCUCUCCACU

4615	2407	AUAACAUAGUAUGCUUCAAAU

4616	2408	CAAGACACAGUCAUGCACAAU

4617	2409	CAGAUAACACAUUCUGACAAA

4618	2410	GUUUAAAUGUGGUUUCUCCUA

4619	2411	AAGCAGCAUAUCUGAGGUGAC

4620	2412	UGGAGUAAUCGUGCCCAUUGC

4621	2413	ACGGUGGAAGUGACCACUUUA

4622	2414	ACCACAACCUCCGCCUCCUGG

4623	2415	AGCAAUGGAUUCAACCACAGA

4624	2416	AUUAGUGGGACUUGCCCUAUU

4625	2417	AGUUUACCCUCUUUCCAGCAG

4626	2418	CCUCUUCAUCUUCUUCUUCAG

4627	2419	AGUGGGACUUGCCCUAUUGGU

4628	2420	GUGUUCCCAGUCUUUGUCCAU

4629	2421	AGGUUCAGAACCUGAACUCAC

4630	2422	GAGGAGGUCAAGCCUCUCCCA

4631	2423	CUGGUUGUUGACUGUUUCUUU

4632	2424	CCUAUGAGGAUUUCCUAGGUU

4633	2425	AAGGGUCACUGCUCCAAGGUC

4634	2426	CUAUUGAAAUUAGUGGGACUU

4635	2427	AAGAGAGAUCUCUGGGCGCUC

4636	2428	AACCCAAAGUCAGUCAAUUUA

4637	2429	CUAAUGAAUAGGGCUUCCUAA

4638	2430	UGGAUAUAUGGAUGGUUAGAU

4639	2431	UCCUAACCAGGUAUUGGGCUC

4640	2432	UCAUGACCAGAAUUUCAUUAA

4641	2433	AUAAAGCCUAUGGAAUAAUUG

4642	2434	CAUCUCCUGAACAUAAACACG

4643	2435	UGAGAUACAAUUCUGAUAAAC

4644	2436	GAUCUCCUCAUCUGUCAUCUU

4645	2437	GUGACUUGCCUAGCGUCACAU

4646	2438	UAGAUGUUAUGAGUAUAAUCC

4647	2439	GUCACUAAUGUACUGAUUUUU

4648	2440	UCCAAGUUUCAAACUGCAAUA

4649	2441	AGCUUCUUUCUAAUACUUAUU

4650	2442	UCCUGGGUUCAAGCGAUUCUC

4651	2443	CGGACUGACAUUUCUUGGGAU

4652	2444	GGAAGAGGUACUUAGAGCCAA

4653	2445	CUUAUCAUCAAUAAUGAAUAU

4654	2446	GACUUCUCUAGGUAUAGGGUC

4655	2447	AGGCUAGUAUUUAUCCCACUA

4656	2448	AGAUGUGCCCUCGUUAUCUCA

4657	2449	UGUAGCCUUCACUGACCUCCC

4658	2450	UAUUCAUUUGAAAGGUAAAGA

4659	2451	AAUGAAUUGGAAGGCUGCCAC

4660	2452	CAAGCCUGAAAGAAAUCUGAA

4661	2453	CUGUGGUUGAGUGCUGAAGAA

4662	2454	AACUGAAUAUUAACUGCAAGU

4663	2455	GUAUGCUCAAAGUCUGAAGGA

4664	2456	AAAUAUCUCAAACUAUCAAAA

4665	2457	CUUGUCCUGUUGCAAUGUCUA

4666	2458	UGAAAGCCCUUCCUGAACACA

4667	2459	AAUAUCCUGUUGGACAAGAAA

4668	2460	UGAGGAUUUCCUAGGUUCAGA

4669	2461	ACAGAAAUAGGUGAUACAUAG

4670	2462	AGAAGCUCAAGUACAGUUAUA

4671	2463	UCUGCUGUAGGCAGGGCAUUG

4672	2464	CUAACUAAUGAAUAGGGCUUC

4673	2465	UACCCAACAUGGUGACUGAUU

4674	2466	AGUCAUUACCCAACAUGGUGA

4675	2467	GAUUUCAGUAUUCUACAUUUA

4676	2468	CUCAACAUGUAAGGGAUGCUA

4677	2469	GGACAUCUAAUGACAAUGCAA

4678	2470	UCUUUCAUAGGAGAAAUAUUC

4679	2471	AUGUAGCCUUCACUGACCUCC

4680	2472	CUUCAUCCAUACAGGUCUCUG

4681	2473	AGGCUUAUAAGAAGUUUCUAU

4682	2474	GCAACAGAUGUUAUCAAGGGG

4683	2475	CAGUAGACAUCACUACCCUGU

4684	2476	CUGCUAUGUAUCCAUGUGCAC

4685	2477	CAAGAGAGGAUUAAUUUAGGU

4686	2478	UGUUUACUAUAUCACCUUUCU

4687	2479	AUCCAAAGCUUGCAGGCACUC

4688	2480	AUGCAUGUUGGGUUAUAUUCA

4689	2481	AUGGACACACAAAUAUUUACA

4690	2482	AUUUCAUUAAUAAUUAAUUCC

4691	2483	CAGUCCUACAUAUUUGUUUAA

4692	2484	UGGUACUGCUGGUGAAGCAAU

4693	2485	ACCAGAUAUCAACUUUCGGAC

4694	2486	AGAAACAGCUUCUUUCUAAUA

4695	2487	GAGGUUUGAAUGCAAGAGGGA

4696	2488	ACCAUAGUGCUUCGUUUACUU

4697	2489	AACUCCCAGUUUACCCUCUUU

4698	2490	AAGAAUCCCGGUUGUUACUAU

4699	2491	CACACAAAUAUUUACAAUGAC

4700	2492	CUGUAUAAACAGUACCUGAUG

4701	2493	UUCCCAGUCCACAUGCAAAUA

4702	2494	GCAAUAUCUGCAACAGAUGUU

4703	2495	CAAAGAACUAAGCAUGAACAC

4704	2496	ACACGAUCUUUGAGCUGAGAA

4705	2497	UCCCAACAAAUUAAUUUGUCA

4706	2498	UGCCCUGCAUGCUCUGCGCUC

4707	2499	UUCUUGGGUUGCUGUUGAAGG

4708	2500	AGGCUUAGAGAAACAACUUUC

4709	2501	CUCAAUGCUAAUAGCAUGUAA

4710	2502	ACAUGGAGGUGAUAUCUCAGU

4711	2503	CAAGUCAUAUAAGGAAUUCUG

4712	2504	ACAUAAGAGACUCAGGCUUAA

4713	2505	AAGUGACCACUUUAUGGUCAC

4714	2506	AGAAGGAGAGAGGCCUAUGUA

4715	2507	UCCUGAACAUAAACACGUACA

4716	2508	GCUGAAUGUACAUAAGUUCUG

4717	2509	ACUGUGGGAGUUGUCAUCAGA

4718	2510	CAUGGGAUUAUGACAACGCAC

4719	2511	CAGCUGCUAUCUGUCCUUCAU

4720	2512	AGAGAAUUUCAAGACAUUUAU

4721	2513	CUGACCUCCCAUUUCUUACAG

4722	2514	UCAGUUUACAAAUGCUGAAUU

4723	2515	AGAUCUUAUCAUCAAUAAUGA

4724	2516	ACUAUAUCACCUUUCUCUAGA

4725	2517	CAUAACUUCUAUUGAAAUUAG

4726	2518	GACUUCCACAUGUUCACACAG

4727	2519	AGCAGAGGGCAGACAACCUGU

4728	2520	ACUCAAUGCAUUAGUAGCUAC

4729	2521	CAUACAGGUCUCUGUGACCAC

4730	2522	CCCAGUAGACAUCACUACCCU

4731	2523	UGUGGGAGUUGUCAUCAGAAA

4732	2524	AUCAAACUGUCAGUUUACAAA

4733	2525	CUAUCAGAUACAAUGCCCUGA

4734	2526	CUUUACAUACAGACUGUAUGG

4735	2527	AGGCCCAUCAAACUGUCAGUU

4736	2528	AGAAUAUUGUCACUCUUUAUA

4737	2529	GAUCCUUCUCAACUUGUUUUG

4738	2530	CAGGAAAUCCAAAGCUUGCAG

4739	2531	CUUUAAUCCAAAGUUACAGAA

4740	2532	ACUCUAUUAGGGCAUGGACUU

4741	2533	UCUCUGCCCUGCAUGCUCUGC

4742	2534	CUAUCUUUGGUUCCCAACAAA

4743	2535	GUUACUAUUCAUCCUCAGUGG

4744	2536	UUCAAGUUACUCGAUUGUACC

4745	2537	UCAUUACCCAACAUGGUGACU

4746	2538	ACAAUAUUAGGGUUCUUAUUU

4747	2539	CAAAUUAAUUUGUCAACAUUU

4748	2540	UUCCACCACCCUAACACAACU

4749	2541	GUUCAGAGCUCAGAGACUGGG

4750	2542	ACUUCUCUAGGUAUAGGGUCU

4751	2543	CAUAUGUUUCAUAAGCACAAG

4752	2544	AACUGUAAAUGAAUUGGAAGG

4753	2545	CAAAGUGCUGGGAUUACAGGU

4754	2546	ACCAAGUAGCUAUCUAAAUAA

4755	2547	GUUAGAAGGAAGUUAUCCUUU

4756	2548	CAGAAGAUUCAGGAAGUGCCA

4757	2549	CACACAUAUUCCUCUCCACUU

4758	2550	GAAACAACUGUAAAUGAAUUG

4759	2551	GAUAUUAUAGAAUCUCUCAGA

4760	2552	GUCUAGUGCUGUAUAAACAGU

4761	2553	AUGCUGAGGUCAGAAGGAUGG

4762	2554	ACCUUUGCUUAACUGAAUAUU

4763	2555	AAGCAAUAUUAUAACAAUAUC

4764	2556	AGGAUCAGGUGGUUAAACUCA

4765	2557	CUAUGGAUCACCUGGUUUGAG

4766	2558	UUCCCACUGCCCUAUUCCUAA

4767	2559	UACACAUGGUUUACAGAUAAC

4768	2560	ACUGCCCUAUUCCUAACUCAG

4769	2561	UGCACAAUCCAUAUUUCAAUU

4770	2562	CAGGAUGUCACAGUUUCAGUU

4771	2563	AACUCACCUAGCAGGAUGUCA

4772	2564	GAUCCUUGCUAACAACAUUAA

4773	2565	CACACCACACACAAGCACACA

4774	2566	AGGAGAAGCUCAAGUACAGUU

4775	2567	CCUGUUGCAAUGUCUAGUGCU

4776	2568	GUUGCAAUGUCUAGUGCUGUA

4777	2569	ACUUGAGUUAAAUCUUCUUAC

4778	2570	GCUAAUAGCAUGUAAUUACUU

4779	2571	UCCUCCUGGUAUGCCUAUUUU

4780	2572	CUGGAUCCUUGCUAACAACAU

4781	2573	UCCCUGACUUUCCCACUGCCC

4782	2574	CAAAUAUCUCAAACUAUCAAA

4783	2575	GUGACCACAUCAGUCAGAGAG

4784	2576	AAUAGGUGAUACAUAGGAAAA

4785	2577	UGCAAAUACACGUUCAGAAUU

4786	2578	GUAUUGGGCUCUCUCCACUGG

4787	2579	AUGUCUAGUGCUGUAUAAACA

4788	2580	GUCUCGAACUCCUGACCUCAG

4789	2581	AAACAACUUUCUGUAAUUUAC

4790	2582	UGGUGAAAUAGUAGUCAAAUU

4791	2583	ACUUUACAUACAGACUGUAUG

4792	2584	UCCCGAGAAGAAUAUUGUCAC

4793	2585	ACAACCUGGUUUACUCAAUUA

4794	2586	UGUUGAUUUCCUCUUGGGUAC

4795	2587	AUAAUUCCACCACCCUAACAC

4796	2588	CCACAUGUUCACACAGUACUU

4797	2589	UGGAGAGGUUAAGUGACUUGC

4798	2590	GAAAGAAAUCUGAAUAACAUA

4799	2591	AUCAUAAGUAAAUGAUGAUUA

4800	2592	GAGCUUUAUUUAGAUAUACAG

4801	2593	AGUUGUCAUCAGAAAUGCUAU

4802	2594	CCGGUUGUUACUAUUCAUCCU

4803	2595	GACAGUCCUACAUAUUUGUUU

4804	2596	CUCCUGGGAAGAUAGAGCGAA

4805	2597	AUGUGCCCUCGUUAUCUCAGG

4806	2598	AGUGACUUCUCUAGGUAUAGG

4807	2599	UGCUGUUUAUUUAUUGUAAAG

4808	2600	GUGGGUUCUUCUUCUGUUCCA

4809	2601	CUUGCCUAGCGUCACAUAGCA

4810	2602	ACCCAGGCAAGCAUAAAGCCU

4811	2603	ACAUAUUUGUUUAAUGAUUUC

4812	2604	GUUAAACUCAAACAUUGGGGU

4813	2605	GCAUCUUUGAGAAACCUUUUU

4814	2606	UGUAAGGGAUGCUAACUAAUG

4815	2607	UUCCAAGUUCCCAUUUAUUUC

4816	2608	GUGCAUCUUUGAGAAACCUUU

4817	2609	CAAGAACGAAGUCAUUACCCA

4818	2610	AGGUCAAGCCUCUCCCAACUU

4819	2611	GUUCAGAACCUGAACUCACCU

4820	2612	CACGGUGGAAGUGACCACUUU

4821	2613	AUCUUGCAAGUUCAACCCAAU

4822	2614	UGGGCUCUGCUAUCUUGUGCC

4823	2615	CUAGGUUCAGAACCUGAACUC

4824	2616	CUAGCGUCACAUAGCAAUUUA

4825	2617	CACAUAUUCCUCUCCACUUUU

4826	2618	CUGAAUGAUAUACAGUAAUAU

4827	2619	AUGACCAGAAUUUCAUUAAUA

4828	2620	CACAGAACGAGUAUAGAUUGA

4829	2621	AAACCCAUUGAGCAAAGGAAU

4830	2622	UGGUACAAAGUGGUAGUAAAG

4831	2623	AACUCUAAAGAAAGUGCUUUC

4832	2624	AACAGAAAGAUUAUAUCAAAA

4833	2625	CUGAACUGAAAGCAUAAGAGA

4834	2626	AAGAUGUGCCCUCGUUAUCUC

4835	2627	UCCCUAGCUUUAACUUAUAGA

4836	2628	CAUUUCUCAAUGCUAAUAGCA

4837	2629	CAAAUUAAUAUUACCGUUUCA

4838	2630	AGCCCUUCCUGAACACACAUA

4839	2631	UAUGGAUCACCUGGUUUGAGU

4840	2632	UGUGGGUUCUUCUUCUGUUCC

4841	2633	AGCUUGCAGGCACUCUCUGCA

4842	2634	AAUAUCAUUUAUAGACAAAUA

4843	2635	CUCCUGAACAUAAACACGUAC

4844	2636	AAUGGAUUCAACCACAGAACG

4845	2637	AAUUUCCCGGCACUAUGAGUG

4846	2638	AGUAUUUAUCCCACUACAUCU

4847	2639	AUUUCACCGUUUGAGCUUUAU

4848	2640	AUUUAGUAAUAAAGCUCAUAU

4849	2641	ACUUGUAAGUGUUUAGGUUCA

4850	2642	CUCUCCAAUACAGGGAAGGGG

4851	2643	CUUUCUAAUACUUAUUAGAAA

4852	2644	UGCCCUCGUUAUCUCAGGGCA

4853	2645	ACUCUAAAGAAAGUGCUUUCA

4854	2646	AUAUUCCGAAACAGAAAUAGG

4855	2647	UCACAAGCCUGAAAGAAAUCU

4856	2648	AGGAUCAUCUAGUCCAAUACA

4857	2649	ACCUCUUUAUUUGGUACUGCU

4858	2650	AUCCCUGUUUAUGUUAUUUAA

4859	2651	AGUUUCAAACUGCAAUAUUUU

4860	2652	AGAUUGGAUGCUGAGGUCAGA

4861	2653	ACACUCAAGACACAGUCAUGC

4862	2654	GUGGAUCCUUCUCAACUUGUU

4863	2655	AUGACUACCCAUAGUUCAUCA

4864	2656	AUAUCACCUUUCUCUAGAUCU

4865	2657	GUUAUAUUCUAGCAAGUGUGA

4866	2658	AAAGCAGAGGGCAGACAACCU

4867	2659	ACAAGGAUUUCAGUAUUCUAC

4868	2660	GAAUGUACAUAAGUUCUGUUU

4869	2661	ACAGAACUAUAACUGAAUGCC

4870	2662	AAUCCUACCUGAAUGAUAUAC

4871	2663	UGAGUUAGAAGGAAGUUAUCC

4872	2664	ACUUAAUGUCCAACAAGGAUU

4873	2665	AAUUUGCAAGGCAACCUAUAA

4874	2666	UCUCUGCAGACAGCUGCUAUC

4875	2667	ACUUGAGAAUUAAACUCUAGA

4876	2668	ACUGCAAGUAGCUUAGAUAAA

4877	2669	CUCUCUCUCAUUAGAGCAGUG

4878	2670	CACAUGAAUCGUAUGCUCAAA

4879	2671	AUCUUGGUACAAAGUGGUAGU

4880	2672	GAGACUGGGAGAUACUUGCAC

4881	2673	UGUAAGGAUCAGGUGGUUAAA

4882	2674	CUUAUUCUUCUCUUCAGGGGC

4883	2675	UCUUACUCAUGAGGGAGAUGG

4884	2676	AAGUUACUCGAUUGUACCAAA

4885	2677	CGGAAUACAGCUGACAGUCUC

4886	2678	UGUGACCUCUUUAUUUGGUAC

4887	2679	GUAUAGAAUACUCGUACACAC

4888	2680	CAUUGUUUAAUAUUAAACACA

4889	2681	UAAGCACAAGAGAGGAUUAAU

4890	2682	CACAUCCAUCUCAAGACAGCG

4891	2683	GAUGUAGCCUUCACUGACCUC

4892	2684	CUUUGUCCAUAUGCAUUUCUU

4893	2685	CAGGGAAAGAGAAUAAACUGU

4894	2686	UAAUGACAAUGCAAGUGAAAA

4895	2687	ACUUCAUUUGCUUGAGUUUUU

4896	2688	CUCAGAGAAAGUCCCAUCUUU

4897	2689	AUCUAUUUCCUCCUGGUAUGC

4898	2690	AGGUAUCAUUAUCUUUGUUUA

4899	2691	CAAAGAUUUGGAUAGACUCAC

4900	2692	UGCUUCUCACCCUUCCCUGAC

4901	2693	UCUGGAAUUCCAGUGAAUUCC

4902	2694	UGCUGAACUGAAAGCAUAAGA

4903	2695	GUAUCAUAAGUAAAUGAUGAU

4904	2696	GUUAUAUUCAUUUGGUCACUU

4905	2697	CAAAGUCAGUCAAUUUAACAG

4906	2698	CACCUUUCUCUAGAUCUUUAA

4907	2699	GUGCAGGAAAUCCAAAGCUUG

4908	2700	GUCAACAUUUCUCAAUGCUAA

4909	2701	CACACACAAGCACACACAUUG

4910	2702	GCUAUCAGAUACAAUGCCCUG

4911	2703	UGUAAUCCCUGUUUAUGUUAU

4912	2704	CUAAGUAUUUCUGUAUUGAGA

4913	2705	ACAGUACUUGCUCUGGUAUUU

4914	2706	ACCAUCCACUAACUCCCAGUU

4915	2707	CAGAAGGAUGGAACCAUACCA

4916	2708	UGGUAUUUGCGGGUCCAUAAA

4917	2709	UGAAUGAUAUACAGUAAUAUC

4918	2710	UGCUUCAACCACAAUUUAAAA

4919	2711	CAUGAUCUCAGCUCACCACAA

4920	2712	CAGUCCUCUUGUUCAGAGCUC

4921	2713	AAUCCCGGUUGUUACUAUUCA

4922	2714	AUAUAAUUAUUUACACGAUCU

4923	2715	GCUGUUCUUAAUUGCUUCCUU

4924	2716	UUGCUGCCCUGUUUGGGCUGC

4925	2717	UCAGGUAUUAAGGAGAUUAAC

4926	2718	UCUCAGGGCACACUAGCAACA

4927	2719	ACUGUUUCUUUGGAAUCAUAG

4928	2720	CUCAGGGCACACUAGCAACAU

4929	2721	CUGUAAAUGAAUUGGAAGGCU

4930	2722	AAGUUACAGAAGAAUUUCACU

4931	2723	AGAGAGGAUUAAUUUAGGUAU

4932	2724	UCUAUUAGGGCAUGGACUUCC

4933	2725	UGGUUCCCAACAAAUUAAUUU

4934	2726	GACAUUUAUGAAUAUGCUUUU

4935	2727	ACCAACAGAAAGAUUAUAUCA

4936	2728	GUUCCUGUACAAAGUACUGGA

4937	2729	ACAUGUUCACACAGUACUUGC

4938	2730	UGCUAAUAGCAUGUAAUUACU

4939	2731	AUAGAUAUAUGGUGAAAUAGU

4940	2732	GUACAGUUAUAUUCUAGCAAG

4941	2733	UAGCGGCUGCUGUUCUUAAUU

4942	2734	CACCGUUUGAGCUUUAUUUAG

4943	2735	ACCAUACCAUCAGCAGGUCUA

4944	2736	CAAGACAUUUAUGAAUAUGCU

4945	2737	GACUGGGAGAUACUUGCACUA

4946	2738	CUUGUAAGUGUUUAGGUUCAC

4947	2739	AGUAAUCGUGCCCAUUGCUCU

4948	2740	UAAGAGACUCAGGCUUAAACG

4949	2741	ACAUGCAAAUACACGUUCAGA

4950	2742	AAUCCAAAGUUACAGAAGAAU

4951	2743	UCUUUCGCUUCACGGUGGAAG

4952	2744	AUGCUCAAAGUCUGAAGGAAG

4953	2745	AUGGAACAUGGACACACAAAU

4954	2746	AUCAACUUUCGGACCAUAAGC

4955	2747	AGUUACAACUAAUUUCACAGC

4956	2748	AGAUAACACAUUCUGACAAAA

4957	2749	UCCAAUACAAAUGCAGAAAAA

4958	2750	AGCUCAUGUAUUUCUGGUUGU

4959	2751	UCCCAGGAUUUCAUUGAAUUU

4960	2752	CGCUCUUUCUCCUUCUUCUUA

4961	2753	ACAGGAAAGGAGAAGCUCAAG

4962	2754	AGAAUAAACUGUUAACAAUCU

4963	2755	CACAGGAAAGGAGAAGCUCAA

4964	2756	UUCCUCCUGGUAUGCCUAUUU

4965	2757	CAUCUUUCCUGCAGCAGAGUU

4966	2758	CUAGGCUAGUAUUUAUCCCAC

4967	2759	AGAAGAAUCCUACCUGAAUGA

4968	2760	ACCCUAACACAACUGAUUUCA

4969	2761	ACUCUCAGAAGAUUCAGGAAG

4970	2762	AGAGAUCUCUGGGCGCUCUUU

4971	2763	AAAUAUCAUUUAUAGACAAAU

4972	2764	UCCCAAUGCAUGUUGGGUUAU

4973	2765	GUUCUAAUAGUGACAUCUCCC

4974	2766	AUAUCCUGUUGGACAAGAAAA

4975	2767	AUUAUAGAAUCUCUCAGAACU

4976	2768	UCAGGCUUACAAAUAAAUUAC

4977	2769	AUCUCUGGGCGCUCUUUCUCC

4978	2770	CUCUCUCAUUAGAGCAGUGUG

4979	2771	CUCAGGUGAUCCGCCUGCCUU

4980	2772	AGGAGUGAUCUGGGCACAGAA

4981	2773	AUUUCCCGGCACUAUGAGUGA

4982	2774	CCAAUCUAAAGCAACCACAAA

4983	2775	CUAAGAUCUCCUCAUCUGUCA

4984	2776	UGGAGGUGAUAUCUCAGUUCC

4985	2777	CUUCCACAUGUUCACACAGUA

4986	2778	AGAUGGAUGGAUGUACCUUGG

4987	2779	ACUGCUGGUAUUAUGGGAUAG

4988	2780	UGCUCUGGUCUUGGUGCGAUA

4989	2781	AAUAUCUCAAACUAUCAAAAC

4990	2782	AACUCUAUUAGGGCAUGGACU

4991	2783	GAAUAUUAACUGCAAGUAGCU

4992	2784	CCAUAAAUACCUUUAAUCCAA

4993	2785	AAGGAUCAGGUGGUUAAACUC

4994	2786	CUCUCUGCAGACAGCUGCUAU

4995	2787	GAGGGAGUGUGCAUCUUUGAG

4996	2788	UCUUAUCAUCAAUAAUGAAUA

4997	2789	UAAUGAAUAGGGCUUCCUAAC

4998	2790	CCUAGGCUAGUAUUUAUCCCA

4999	2791	AACUUUCUGUAAUUUACAAAA

5000	2792	AUUGAGCAAAGGAAUAUAAUU

5001	2793	AUUCUGAUAAACAAUGAAAAC

5002	2794	AGGCAGAGACAGUCCUACAUA

5003	2795	ACACAGGUGUGCACAUGGAGG

5004	2796	AUUAGGGCAUGGACUUCCACA

5005	2797	GACCAAGAGAUUCAACCGGGG

5006	2798	AGAAAUGCUAUCUUUGGUUCC

5007	2799	GUAAGUGUUUAGGUUCACUCU

5008	2800	AGCAUGAACACACCAUAUUCC

5009	2801	CCAACAGAAAGAUUAUAUCAA

5010	2802	ACCUGAAUGAUAUACAGUAAU

5011	2803	AAGGGAUGCUAACUAAUGAAU

5012	2804	CACAGGUGUGCACAUGGAGGU

5013	2805	CUUCUCAACAUGUAAGGGAUG

5014	2806	UGCUGGUAUUAUGGGAUAGCA

5015	2807	CUGGAGAGAAUUUCAAGACAU

5016	2808	GAAGAAUCCUACCUGAAUGAU

5017	2809	AUGUAAAGCUCAUGUAUUUCU

5018	2810	AUAGUAUGCUUCAAAUUAAUA

5019	2811	AUGGUGAAAUAGUAGUCAAAU

5020	2812	GUCUCUGUGACCACAUCAGUC

5021	2813	GCAUGAACACACCAUAUUCCG

5022	2814	CUUGGUACAAAGUGGUAGUAA

5023	2815	CAUGGGCUCUGCUAUCUUGUG

5024	2816	GCCUAUGUAACUGAUCUCUUU

5025	2817	AAAGAGAAUAAACUGUUAACA

5026	2818	AGUUAGACAUUGUUUAAUAUU

5027	2819	ACCCACCAAGUAGCUAUCUAA

5028	2820	GAUGCUAACUAAUGAAUAGGG

5029	2821	CUAUUCCUAACUCAGGACAUU

5030	2822	AGGAAGUUAUCCUUUGGUUAG

5031	2823	AUGGUGAGGUGUAAGGCUUGC

5032	2824	UCUGGGCGCUCUUUCUCCUUC

5033	2825	AGCUCACCACAACCUCCGCCU

5034	2826	UCAGUUAGACAUUGUUUAAUA

5035	2827	CAGUCUUUGUCCAUAUGCAUU

5036	2828	UUCAUCCUCAGUGGAGGAGCC

5037	2829	ACUGUAAAUGAAUUGGAAGGC

5038	2830	AGUAAAUGAUGAUUAAUGUAU

5039	2831	AGUAAUAAAGCUCAUAUUAGA

5040	2832	UCCUAGGUUCAGAACCUGAAC

5041	2833	AUGCUACAAGUUGUAUAGAAU

5042	2834	GAUACAAUUCUGAUAAACAAU

5043	2835	CAGAGGGCAGACAACCUGUUU

5044	2836	GCUUGCAGGCACUCUCUGCAG

5045	2837	AGUCACCACCUCAGGUGCCAU

5046	2838	CUGCCCUGCAUGCUCUGCGCU

5047	2839	GGGACCAUCCACUAACUCCCA

5048	2840	CAUUAGUAGCUACAGGAUUCU

5049	2841	AGGCAAUAUCUGCAACAGAUG

5050	2842	AGGAUUAAUUUAGGUAUCAUU

5051	2843	GAUUCAACCACAGAACGAGUA

5052	2844	CAUCACAUUGGGUAAGGAGUU

5053	2845	UGUUGACUGUUUCUUUGGAAU

5054	2846	ACAAAUGCUGAAUUUCAGUCC

5055	2847	UGAGUAUAAUCCCAGUAGACA

5056	2848	UGUGCUGAGUUCACUUCAAAU

5057	2849	ACCACCCUAACACAACUGAUU

5058	2850	CUACUCUCAGAAGAUUCAGGA

5059	2851	CAAAGCUUGCAGGCACUCUCU

5060	2852	GAAACAACUUUCUGUAAUUUA

TABLE 7

Results for TRNP1. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID		siRNA guide strand/
NO	siRNA_id	AS Sequence

5061	1	UUUAAUGAGGAAGACUUCCUG

5062	2	UCAAUUCUCAACGUCUUCCUG

5063	3	UUGUUUAAGAAUGAUGACGAU

5064	4	UAAUCUGAUUGCAUCUCAGGG

5065	5	UUAGACUUGAAGCAAUGACAU

5066	6	UUAAUGAGGAAGACUUCCUGA

5067	7	UAAUUCAAUAUACAUUCACUA

5068	8	UAUGGAAAUUUAUUCCUCCUG

5069	9	AACGAAACUAAAUACAAGCUG

5070	10	UAGAGUGGAGGUUCUGAGGAG

5071	11	AUGCUUGCUACGCUUAAUCUG

5072	12	UGUAGCAACAUCUCCAAUUGU

5073	13	UAGGAGUCAAGGUCGGAGUUG

5074	14	UUAAUCUGAUUGCAUCUCAGG

5075	15	UAAUGAGGAAGACUUCCUGAG

5076	16	UAAGGCAGGAGACUAAUUCAA

5077	17	AUCCGUAGUCCUUCCAGCCGG

5078	18	UAGACUUGAAGCAAUGACAUC

5079	19	UGUAAGGUCAAUUCUCAACGU

5080	20	AACAUCUCCAAUUGUACAGUG

5081	21	UAUAUGAAGAAAUUCAGAGCA

5082	22	AAUCUGAUUGCAUCUCAGGGA

5083	23	UCAAUAUACAUUCACUAUGCA

5084	24	ACUAAAUACAAGCUGCUCCAG

5085	25	AAUUCUACAAGUUCUGGGCUA

5086	26	UUGGUCUGCAAAUCAAAGUCA

5087	27	UGCAGAAUUCUACAAGUUCUG

5088	28	UGAAGCAAUGACAUCUAUUAA

5089	29	UGGUCUGCAAAUCAAAGUCAA

5090	30	UUAUGGAAAUUUAUUCCUCCU

5091	31	UAUACAUUCACUAUGCAGAAU

5092	32	UCACUAUGCAGAAUUCUACAA

5093	33	UUGCAUCUCAGGGACCUGUAG

5094	34	AGGAUGACCACAGCACACCCG

5095	35	UAAAGUGAAAGGCUCCUGUGA

5096	36	AAGAAUGAUGACGAUAUCUUG

5097	37	AUAGACACAGAGGAAAGGCAG

5098	38	UGAAGAAAUUCAGAGCAUCAG

5099	39	UGAUUGCAUCUCAGGGACCUG

5100	40	UUAUCAGGAUGUUUAAAUGUG

5101	41	ACUUGAAGCAAUGACAUCUAU

5102	42	AUAUGAAGAAAUUCAGAGCAU

5103	43	UCGGUCGGUCGGCACCUCGGC

5104	44	AUCCAUAGAGUGGAGGUUCUG

5105	45	AAUCCAGAGGUCCAGAUCCAU

5106	46	UGCAAAUCAAAGUCAACAGGG

5107	47	UCUUCCUGAAGGCAGUGCCCA

5108	48	UACAAGCUGCUCCAGGAACCG

5109	49	UUGAAGCAAUGACAUCUAUUA

5110	50	AAGGUCAAUUCUCAACGUCUU

5111	51	AUAUACAUUCACUAUGCAGAA

5112	52	UCAACGUCUUCCUGAAGGCAG

5113	53	AAGCCGAAUCCAGAGGUCCAG

5114	54	AUGAGGAAGACUUCCUGAGGA

5115	55	AUCACAUCCUUUAAUGAGGAA

5116	56	UCCUGCGGAUCCGUAGUCCUU

5117	57	UUGGAAGGAGCUCAGCCUCCU

5118	58	AUAGAGUGGAGGUUCUGAGGA

5119	59	AAUCAAAGUCAACAGGGCCAG

5120	60	AAAUACAAGCUGCUCCAGGAA

5121	61	UCAGUCGGUCGGUCGGCACCU

5122	62	ACAAGCUGCUCCAGGAACCGU

5123	63	UGAGGAAGACUUCCUGAGGAG

5124	64	AAAGUGAACCUCAGAACCCCA

5125	65	CAAUUGUACAGUGUAAGCCAA

5126	66	ACCUCGGCGAAGCUUGUCGGG

5127	67	UGGAAAUUUAUUCCUCCUGAA

5128	68	UAAGAAUGAUGACGAUAUCUU

5129	69	UUAAGAAUGAUGACGAUAUCU

5130	70	UAAAUACAAGCUGCUCCAGGA

5131	71	AAUUUAUUCCUCCUGAAUGUA

5132	72	ACUAAUUCAAUAUACAUUCAC

5133	73	AACGUCUUCCUGAAGGCAGUG

5134	74	AACUAAAUACAAGCUGCUCCA

5135	75	UCCUCCUGAAUGUAUAAGGCA

5136	76	AUUCAAUAUACAUUCACUAUG

5137	77	AAUUCAAUAUACAUUCACUAU

5138	78	UAAUAGACACAGAGGAAAGGC

5139	79	UAUGCAGAAUUCUACAAGUUC

5140	80	AUCUCCAAUUGUACAGUGUAA

5141	81	CAAUAUACAUUCACUAUGCAG

5142	82	UUGCUACGCUUAAUCUGAUUG

5143	83	CUUAAUCUGAUUGCAUCUCAG

5144	84	UUCACUAUGCAGAAUUCUACA

5145	85	ACCGUCAACUUAAAGAGCCAU

5146	86	UUCCUGCGGAUCCGUAGUCCU

5147	87	AUUCUCAACGUCUUCCUGAAG

5148	88	UCAAGGGAGAAUUGGUCUGCA

5149	89	UGCGGAUCCGUAGUCCUUCCA

5150	90	UCUGCAAAUCAAAGUCAACAG

5151	91	UUGCCUUACAUUAUGGAAAUU

5152	92	AGCUGCUCCAGGAACCGUCAA

5153	93	AACCGUCAACUUAAAGAGCCA

5154	94	UGCUCCAGGAACCGUCAACUU

5155	95	UGCCUCUUCCUGCGGAUCCGU

5156	96	ACCUGUAGCAACAUCUCCAAU

5157	97	UCCAGCUCCGACACCAGGCGC

5158	98	UCUGCGGCUGUAGGUGCGCAG

5159	99	AAUUCUCAACGUCUUCCUGAA

5160	100	AGAAAUUCAGAGCAUCAGCCA

5161	101	UAUUCCUCCUGAAUGUAUAAG

5162	102	UGGAGAACAAGGGCAGUGGAU

5163	103	UUAAGAAUGUUGUUUAAGAAU

5164	104	UAAGGUCAAUUCUCAACGUCU

5165	105	GACCUGUAGCAACAUCUCCAA

5166	106	UGCAGCUGCAGCACGCGGCUC

5167	107	CAGAAUUCUACAAGUUCUGGG

5168	108	AUGUUGUUUAAGAAUGAUGAC

5169	109	UGCUUGCUACGCUUAAUCUGA

5170	110	UUCAAUAUACAUUCACUAUGC

5171	111	UAGCAACAUCUCCAAUUGUAC

5172	112	UCCAAUUGUACAGUGUAAGCC

5173	113	UUAUUCCUCCUGAAUGUAUAA

5174	114	UUCUUGAGGCGCGACCCGUGA

5175	115	UGUUGUUUAAGAAUGAUGACG

5176	116	AAAGUGAAAGGCUCCUGUGAG

5177	117	AAAUCAAAGUCAACAGGGCCA

5178	118	AGAAUGUUGUUUAAGAAUGAU

5179	119	UGGAGGUUCUGAGGAGUUGGA

5180	120	ACAUUAUGGAAAUUUAUUCCU

5181	121	AUCUGAUUGCAUCUCAGGGAC

5182	122	UAUGAAGAAAUUCAGAGCAUC

5183	123	UUACAUUAUGGAAAUUUAUUC

5184	124	AAUGAUGACGAUAUCUUGAAA

5185	125	ACAUCUCCAAUUGUACAGUGU

5186	126	UGGAGGUCAGCGCUGCGGGGA

5187	127	GAAAUUCAGAGCAUCAGCCAG

5188	128	UCCACCUCCAGCAGCCGCCGC

5189	129	UCUUGAGGCGCGACCCGUGAG

5190	130	UGCAUUUGCCUUACAUUAUGG

5191	131	AUGCAUUUGCCUUACAUUAUG

5192	132	UACAUUAUGGAAAUUUAUUCC

5193	133	UGUAAAGUGAAAGGCUCCUGU

5194	134	UCCGUAGUCCUUCCAGCCGGC

5195	135	AAACGAAACUAAAUACAAGCU

5196	136	UCUCCAAUUGUACAGUGUAAG

5197	137	UCCGCGAUCAGUCGGUCGGUC

5198	138	UGGAAGGAGCUCAGCCUCCUC

5199	139	AUAAUAGACACAGAGGAAAGG

5200	140	AUGGAAAUUUAUUCCUCCUGA

5201	141	UCUUCCUGCGGAUCCGUAGUC

5202	142	AUUGCAUCUCAGGGACCUGUA

5203	143	UCCUGAAUGUAUAAGGCAGGA

5204	144	UUCUCAACGUCUUCCUGAAGG

5205	145	AGAAUGAUGACGAUAUCUUGA

5206	146	AUUAUCAGGAUGUUUAAAUGU

5207	147	UCCGUCAUCACAUCCUUUAAU

5208	148	CACCCGAACAGCUAGACACGG

5209	149	AAUAGACACAGAGGAAAGGCA

5210	150	UCCUUUAAUGAGGAAGACUUC

5211	151	GUAAGGUCAAUUCUCAACGUC

5212	152	UUCUACAAGUUCUGGGCUAUG

5213	153	AUGCAGAAUUCUACAAGUUCU

5214	154	UCCCUCAAACAGGCCUCCCGG

5215	155	UUCCUGAAGGCAGUGCCCAGG

5216	156	GUAGCAACAUCUCCAAUUGUA

5217	157	UUUAUUCCUCCUGAAUGUAUA

5218	158	AUUCACUAUGCAGAAUUCUAC

5219	159	ACAUUCACUAUGCAGAAUUCU

5220	160	UACGCUUAAUCUGAUUGCAUC

5221	161	CAAUUCUCAACGUCUUCCUGA

5222	162	UCCGACACCAGGCGCCGGCGG

5223	163	CACAGCACACCCGAACAGCUA

5224	164	UCCCACGUGGAGAACAAGGGC

5225	165	AAUGAGGAAGACUUCCUGAGG

5226	166	ACAAGCACACUCCCACGUGGA

5227	167	UCCAGAUCCAUAGAGUGGAGG

5228	168	AAGAAUGUUGUUUAAGAAUGA

5229	169	CUAUGCAGAAUUCUACAAGUU

5230	170	UUCCUCCUGAAUGUAUAAGGC

5231	171	UGAGGAGUUGGAAGGAGCUCA

5232	172	UCCAUAGAGUGGAGGUUCUGA

5233	173	UGUUUAAGAAUGAUGACGAUA

5234	174	UUUAAGAAUGAUGACGAUAUC

5235	175	AUGUAUAAGGCAGGAGACUAA

5236	176	CUACGCUUAAUCUGAUUGCAU

5237	177	UCCUGGUCCUCGGCCGCGCCU

5238	178	ACUUGCAAAGUGAACCUCAGA

5239	179	AUUGGUCUGCAAAUCAAAGUC

5240	180	CAUCUCAGGGACCUGUAGCAA

5241	181	UGAGGCGCGACCCGUGAGCCG

5242	182	UAGGUGCGCAGGGAGGAUGAC

5243	183	AGUCGGUCGGUCGGCACCUCG

5244	184	AAACUAAAUACAAGCUGCUCC

5245	185	CAGAGGUCCAGAUCCAUAGAG

5246	186	UCCAUUAUCAGGAUGUUUAAA

5247	187	ACAGCACACCCGAACAGCUAG

5248	188	UAAGAAUGUUGUUUAAGAAUG

5249	189	AGUUGGAAGGAGCUCAGCCUC

5250	190	UCAGGUCAAGGGAGAAUUGGU

5251	191	UGCGGCUGUAGGUGCGCAGGG

5252	192	UCCUGUGAGGAGGGCGCUGGG

5253	193	UCACAUCCUUUAAUGAGGAAG

5254	194	AUUCUACAAGUUCUGGGCUAU

5255	195	AUUUAUUCCUCCUGAAUGUAU

5256	196	UCGGUCGGCACCUCGGCGAAG

5257	197	GAAACUAAAUACAAGCUGCUC

5258	198	GUCCGCGAUCAGUCGGUCGGU

5259	199	UCUGAGGAGUUGGAAGGAGCU

5260	200	UGAAUGUAUAAGGCAGGAGAC

5261	201	UCCAGGAACCGUCAACUUAAA

5262	202	UAGACACAGAGGAAAGGCAGC

5263	203	AGCUCCGACACCAGGCGCCGG

5264	204	AAAUUUAUUCCUCCUGAAUGU

5265	205	ACCUCUGCUCUGCCGUCCCCU

5266	206	UUGCAAAGUGAACCUCAGAAC

5267	207	UGCAGCUCCUGGUCCUCGGCC

5268	208	CUGUAAAGUGAAAGGCUCCUG

5269	209	UGAAAGGCUCCUGUGAGGAGG

5270	210	AUGAUGACGAUAUCUUGAAAA

5271	211	AUCCUUUAAUGAGGAAGACUU

5272	212	AUUAUGGAAAUUUAUUCCUCC

5273	213	AAUGUAUAAGGCAGGAGACUA

5274	214	AGACUUGAAGCAAUGACAUCU

5275	215	UAUAAGGCAGGAGACUAAUUC

5276	216	AGGUCAAUUCUCAACGUCUUC

5277	217	GAAUUCUACAAGUUCUGGGCU

5278	218	AGAAUUGGUCUGCAAAUCAAA

5279	219	CAAAGUGAACCUCAGAACCCC

5280	220	GAGAAUUGGUCUGCAAAUCAA

5281	221	AGGAACCGUCAACUUAAAGAG

5282	222	ACAGAGGAAAGGCAGCAAGGG

5283	223	CUGCAAAUCAAAGUCAACAGG

5284	224	UCAGGGACCUGUAGCAACAUC

5285	225	UCAUCACAUCCUUUAAUGAGG

5286	226	CAGACUAUCUUUCUGAGGGGC

5287	227	UUUGCCUUACAUUAUGGAAAU

5288	228	AGAAUUCUACAAGUUCUGGGC

5289	229	GAUCCGUAGUCCUUCCAGCCG

5290	230	UACAUUCACUAUGCAGAAUUC

5291	231	AGCAGACUAUCUUUCUGAGGG

5292	232	CUGUGAGUCAGGUCAAGGGAG

5293	233	ACUGUAAAGUGAAAGGCUCCU

5294	234	GACUUGAAGCAAUGACAUCUA

5295	235	CACUUGCAAAGUGAACCUCAG

5296	236	CAGAUCCAUAGAGUGGAGGUU

5297	237	CUCAACGUCUUCCUGAAGGCA

5298	238	AGGUCCAGAUCCAUAGAGUGG

5299	239	GUCAUCACAUCCUUUAAUGAG

5300	240	AGCUCAGCCUCCUCUACUGGG

5301	241	AGAACAAGGGCAGUGGAUGAA

5302	242	GCAGACUAUCUUUCUGAGGGG

5303	243	UCAGCCUCCUCUACUGGGCCC

5304	244	CAUCUCCAAUUGUACAGUGUA

5305	245	CAGUCGGUCGGUCGGCACCUC

5306	246	GUAGGAGUCAAGGUCGGAGUU

5307	247	AAGGCAGCAAGGGCACUUGCA

5308	248	AAUAUACAUUCACUAUGCAGA

5309	249	UAGUCCUUCCAGCCGGCGUCC

5310	250	AGCAAGGGCACUUGCAAAGUG

5311	251	AAAGGCUCCUGUGAGGAGGGC

5312	252	UCUCCAGCUCCGACACCAGGC

5313	253	UCCUCGGCCGCGCCUGCUGAA

5314	254	GUAAAGUGAAAGGCUCCUGUG

5315	255	UGGUCCUCGGCCGCGCCUGCU

5316	256	UCUCAACGUCUUCCUGAAGGC

5317	257	UCCCUCCAUUAUCAGGAUGUU

5318	258	CAUUAUGGAAAUUUAUUCCUC

5319	259	AUAAGGCAGGAGACUAAUUCA

5320	260	UGCUACGCUUAAUCUGAUUGC

5321	261	ACAUCCUUUAAUGAGGAAGAC

5322	262	AAUUGGUCUGCAAAUCAAAGU

5323	263	GAUGACCACAGCACACCCGAA

5324	264	ACCUCCAGCAGCCGCCGCCGU

5325	265	CAAGGGAGAAUUGGUCUGCAA

5326	266	UGCGGCGGAAGGGCGAGUCGG

5327	267	AGUUCUCCAGAACCAGCCCCU

5328	268	UCAGGCUCUCCGCGCGGUGCG

5329	269	UGUAUAAGGCAGGAGACUAAU

5330	270	UGUGAGUCAGGUCAAGGGAGA

5331	271	CAACAUCUCCAAUUGUACAGU

5332	272	UCCUUCCAGCCGGCGUCCGCG

5333	273	AAGAAAUUCAGAGCAUCAGCC

5334	274	GACCACAGCACACCCGAACAG

5335	275	AAAGCCGAAUCCAGAGGUCCA

5336	276	UCUGAUUGCAUCUCAGGGACC

5337	277	GCAACAUCUCCAAUUGUACAG

5338	278	GUCAAUUCUCAACGUCUUCCU

5339	279	AGCUCCUGGUCCUCGGCCGCG

5340	280	ACAAGGGCAGUGGAUGAAGGG

5341	281	AAUGUUGUUUAAGAAUGAUGA

5342	282	AGGGACCUGUAGCAACAUCUC

5343	283	UGUAGGUGCGCAGGGAGGAUG

5344	284	GUUCUGAGGAGUUGGAAGGAG

5345	285	AUACAUUCACUAUGCAGAAUU

5346	286	ACACCCGAACAGCUAGACACG

5347	287	CUGAGGAGUUGGAAGGAGCUC

5348	288	AGACACAGAGGAAAGGCAGCA

5349	289	AGUCAAGGUCGGAGUUGGGGG

5350	290	CUAAAUACAAGCUGCUCCAGG

5351	291	AGCGCUGCAGCUCCUGGUCCU

5352	292	UCCAGAGGUCCAGAUCCAUAG

5353	293	ACGUGGAGAACAAGGGCAGUG

5354	294	CAUCACAUCCUUUAAUGAGGA

5355	295	CGAAACUAAAUACAAGCUGCU

5356	296	AGUCCUUCCAGCCGGCGUCCG

5357	297	AAGUGAAAGGCUCCUGUGAGG

5358	298	AAGGAGCUCAGCCUCCUCUAC

5359	299	AGUGGAGGUUCUGAGGAGUUG

5360	300	GGACCUGUAGCAACAUCUCCA

5361	301	ACGCUUAAUCUGAUUGCAUCU

5362	302	CUCAGGGACCUGUAGCAACAU

5363	303	GGCACUUGCAAAGUGAACCUC

5364	304	CACCUCGGCGAAGCUUGUCGG

5365	305	AAGGCUCCUGUGAGGAGGGCG

5366	306	UCUACAAGUUCUGGGCUAUGU

5367	307	AGCUGCGUCCGGCAGCGGCGG

5368	308	AAGCUGCUCCAGGAACCGUCA

5369	309	AAUGCUUGCUACGCUUAAUCU

5370	310	CUUGCUACGCUUAAUCUGAUU

5371	311	AGGAAGACUUCCUGAGGAGGG

5372	312	CCAAUUGUACAGUGUAAGCCA

5373	313	CACUAUGCAGAAUUCUACAAG

5374	314	CUUGAAGCAAUGACAUCUAUU

5375	315	GUGGAGGUCAGCGCUGCGGGG

5376	316	AGCAACAUCUCCAAUUGUACA

5377	317	ACGAAACUAAAUACAAGCUGC

5378	318	AAGGGCGAGUCGGGCUCGGGG

5379	319	UAAGAGCAGGCGGCUGUGAGU

5380	320	UCCAGCAGCCGCCGCCGUGCU

5381	321	AAGGGCAGUGGAUGAAGGGAA

5382	322	AGUGGAUGAAGGGAACGGGGA

5383	323	CUGAUUGCAUCUCAGGGACCU

5384	324	AUUUGCCUUACAUUAUGGAAA

5385	325	AAACAGGCCUCCCGGCGCCGU

5386	326	UCAAACAGGCCUCCCGGCGCC

5387	327	AAGCACACUCCCACGUGGAGA

5388	328	AAGGGAGAAUUGGUCUGCAAA

5389	329	GAAUGAUGACGAUAUCUUGAA

TABLE 8

Results for APLN. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID		siRNA guide strand/
NO	siRNA_id	AS Sequence

5390	1	UUACAAACAUUGAACACAGGG

5391	2	UUUACAAACAUUGAACACAGG

5392	3	UUUCUUAAUGAACAGGGCCUU

5393	4	AUAUUUACACAGAACAAUCUU

5394	5	UAUUUACACAGAACAAUCUUU

5395	6	UAGUAUAAGAAUCAUAAACAA

5396	7	UAUAAAGACAUAUUUACACAG

5397	8	UACAAACAUUGAACACAGGGG

5398	9	UUCAUCAAGCAACUCUACUUU

5399	10	UAGGUCUCCAAAGUCAGUCCA

5400	11	UAUCUUUGUAUAAAUUAGUAU

5401	12	UUAUAUUGAACUCUUUGCAUU

5402	13	UUGACCUAGAACCGAUUUGGG

5403	14	AUAAGAAUCAUAAACAACCAC

5404	15	UCUUGUCUUCUCUUUCUCCCU

5405	16	UAACUAGAGUCUCUCCUUGCU

5406	17	UAUUAGAGUACCCUGGGUCUG

5407	18	UAUCAAAUGUAUUUAUUGCUG

5408	19	UCUUAACUAGAGUCUCUCCUU

5409	20	ACAAUCUUUACAAACAUUGAA

5410	21	UUCUUCAAAUGACACUGCCAA

5411	22	UAUAAGAAUCAUAAACAACCA

5412	23	AACUAGAGUCUCUCCUUGCUU

5413	24	AUGUUCUUAAAUAAACUGCUU

5414	25	UUUAAGCAGCAGCAGCAGCAG

5415	26	AACAGGACAGUUCACAGCCAG

5416	27	UUAUGGAACCUUCCAGCCCAG

5417	28	UGGAGGAGACAUAACCGCCGG

5418	29	AAUCAUCCAAACUACAGCCAG

5419	30	UUUAUUAUAAAGACAUAUUUA

5420	31	AUAAAUUAGUAUAAGAAUCAU

5421	32	UAUAUUGAACUCUUUGCAUUU

5422	33	UUCUGUUCCUUUGCUUUCUUU

5423	34	UUAACUGAGCAAACGCUGAUG

5424	35	UACACAGAACAAUCUUUACAA

5425	36	UAAAGACAUAUUUACACAGAA

5426	37	ACAAACAUUGAACACAGGGGA

5427	38	UCUAACAUUCUGUGAUUCUUG

5428	39	UGAGCCUUUAAGCAGCAGCAG

5429	40	UUAUCAAAUGUAUUUAUUGCU

5430	41	UAUGUUCUUAAAUAAACUGCU

5431	42	UACAAACAAAGUCAUUAUCAA

5432	43	UAAAUUAGUAUAAGAAUCAUA

5433	44	UCAUCAAGCAACUCUACUUUG

5434	45	UGUUCUUAAAUAAACUGCUUU

5435	46	UUGAGCGGUAGUCUCAGUGCC

5436	47	UAAGUGACCUUCAAGGGUCCU

5437	48	UCUUCUGUUCCCUAUCUCCCA

5438	49	UUACACAGAACAAUCUUUACA

5439	50	UUAACUAGAGUCUCUCCUUGC

5440	51	UUCUCUUUCUCCCUCCUGGGA

5441	52	AACAAUUUCUUAAUGAACAGG

5442	53	UAUUGAACUCUUUGCAUUUUA

5443	54	UCAGCUCUAACAUUCUGUGAU

5444	55	AGAAUCAUAAACAACCACUUU

5445	56	UGACCUAGAACCGAUUUGGGA

5446	57	UUGUGAGAGAACGGGAAUCAU

5447	58	UUCCCUUCCUUCUUCUCCCCU

5448	59	UCAAGCAACUCUACUUUGUGA

5449	60	UUCCUGCUGCACUUCCUCCCA

5450	61	AUCUUUACAAACAUUGAACAC

5451	62	UUGGGAGGCACACUAAGGCAA

5452	63	UUGUAUAAAUUAGUAUAAGAA

5453	64	UUCCAGCCCAUUCCCAUCGGG

5454	65	UCUUUCUUUCCUUCCUUCUGU

5455	66	AUAGCAGAAGACACCCACCAA

5456	67	UCAGGCUCUUGUCUUCUCUUU

5457	68	UAAACAACCACUUUAAAUAAG

5458	69	UGUCAGCUCUAACAUUCUGUG

5459	70	UUCUUAAAUAAACUGCUUUAA

5460	71	UAAUAUCUUUGUAUAAAUUAG

5461	72	AUGGAGGAGACAUAACCGCCG

5462	73	UUAAGCAUAGGGAUUCAUUUU

5463	74	UUAAUAUCUUUGUAUAAAUUA

5464	75	AUAUUGAACUCUUUGCAUUUU

5465	76	UCUACCUCUCCCUUAACUGAG

5466	77	AUAUCUUUGUAUAAAUUAGUA

5467	78	AUCAAGCAACUCUACUUUGUG

5468	79	UCAAAUGUAUUUAUUGCUGAA

5469	80	UAGCAGAAGACACCCACCAAG

5470	81	UCCUGCUGCACUUCCUCCCAU

5471	82	UCUCCCAGCUUUCUUAGCCAU

5472	83	AAGAAUCAUAAACAACCACUU

5473	84	AUCUUUCUUUCCUUCCUUCUG

5474	85	AUUCUUGUGAGAGAACGGGAA

5475	86	AUUUACACAGAACAAUCUUUA

5476	87	AUUCUUCAAAUGACACUGCCA

5477	88	UUGUCUUCUCUUUCUCCCUCC

5478	89	UCAGGCUAUCUCAUUCAUCAA

5479	90	UUCUUAAUGAACAGGGCCUUA

5480	91	UUAGAGUACCCUGGGUCUGGG

5481	92	UGGAGCUUGGGCUAGCUGGGG

5482	93	UAGAGUACCCUGGGUCUGGGA

5483	94	UGGACUGGACGGAUUCUUGUG

5484	95	UUGAAGGCUACCUCGGACUCC

5485	96	UCUGCAAUGACUCUGAGCAGG

5486	97	UCAAGGGUCCUGUCAGCUCUA

5487	98	UAAGCAUAGGGAUUCAUUUUG

5488	99	UUGCCUAAGAAGGCUAAGUGA

5489	100	UUUCCUUCCUUCUGUUCCUUU

5490	101	UGAGCGGUAGUCUCAGUGCCU

5491	102	CUUAACUAGAGUCUCUCCUUG

5492	103	UUUACACAGAACAAUCUUUAC

5493	104	UAGUCUCAGUGCCUGAGCCGC

5494	105	UCUAUGGAGGAGACAUAACCG

5495	106	UUCAAGGGUCCUGUCAGCUCU

5496	107	UAUGGAGGAGACAUAACCGCC

5497	108	UGUGACCUGGUCAUUAAGCAU

5498	109	UUCUGCAGCCUCCUCUCCCGC

5499	110	UUUCUUUCCUUCCUUCUGUUC

5500	111	UAAGGGCGAACUGUCAGCUUU

5501	112	UGAGAGAACGGGAAUCAUCCA

5502	113	AUGCAGGCACUUACCUCCCUG

5503	114	UGACCCUCUGGGCUGCACCAG

5504	115	UCAUUCAUCAAGCAACUCUAC

5505	116	UAACUGUUUAUUAUAAAGACA

5506	117	AUUCAUCAAGCAACUCUACUU

5507	118	UUCCUUCUGUUCCUUUGCUUU

5508	119	AUCAAAUGUAUUUAUUGCUGA

5509	120	UAGAACCGAUUUGGGAUGCAG

5510	121	AAGUAGGAGAUGGGAGACCUG

5511	122	UAAGAAUCAUAAACAACCACU

5512	123	UAGCCCACCCACUACCCUCUU

5513	124	AUCAGGCUCUUGUCUUCUCUU

5514	125	UUUCCUCCGACCUCCCUGCCA

5515	126	UUGGGCAUCAGGCUCUUGUCU

5516	127	AACAAUCUUUACAAACAUUGA

5517	128	UCUUUACAAACAUUGAACACA

5518	129	UGUCUUCUCUUUCUCCCUCCU

5519	130	UCAUUAAGCAUAGGGAUUCAU

5520	131	UUAAUCAGUAUGUUCUUAAAU

5521	132	UACCUCUCCCUUAACUGAGCA

5522	133	AUUUCUUAAUGAACAGGGCCU

5523	134	UCCCUUAACUGAGCAAACGCU

5524	135	UUAAGCAGCAGCAGCAGCAGC

5525	136	UUAUAAAGACAUAUUUACACA

5526	137	UCUUUGUAUAAAUUAGUAUAA

5527	138	UUGGGAUGCAGGCACUUACCU

5528	139	UGAGCAAACGCUGAUGCUCCA

5529	140	UAGAGUCUCUCCUUGCUUUUC

5530	141	AAGCAGCAGCAGCAGCAGCAG

5531	142	AGUGACAAAGGACUUCACGGG

5532	143	AAGAGAAGUGACAAAGGACUU

5533	144	UUCAUGCUGCUCCUUGGGCCG

5534	145	UGCUGCACUUCCUCCCAUCUU

5535	146	UCUCAUUCAUCAAGCAACUCU

5536	147	AUCUCAUUCAUCAAGCAACUC

5537	148	AAUUUCUUAAUGAACAGGGCC

5538	149	AGUAUGUUCUUAAAUAAACUG

5539	150	UAAGCAGCAGCAGCAGCAGCA

5540	151	AGACAUAUUUACACAGAACAA

5541	152	UUAGAUGAGACAGGCAGGGAC

5542	153	UGAACAGGGCCUUAAUAUCUU

5543	154	AUAAAGACAUAUUUACACAGA

5544	155	ACACAGAACAAUCUUUACAAA

5545	156	UAGGACACCCAAACAGAUGCC

5546	157	UCCUCCCAUCUUUCUUUCCUU

5547	158	UAGGAGAUGGGAGACCUGGUC

5548	159	UGAACAUGACCUCCAAGAGUA

5549	160	UGCAAUGACUCUGAGCAGGUC

5550	161	UCUCCAAAGUCAGUCCAGGGA

5551	162	AGCAGCAGCAGCAGCAGCGUU

5552	163	UUCAGAAAGGCAUGGGUCCCU

5553	164	UCUUUCCUUCCUUCUGUUCCU

5554	165	AGUGAUUGAAGGCUACCUCGG

5555	166	AUUCCUUGACCCUCUGGGCUG

5556	167	UAAGGCAAGAGAAGUGACAAA

5557	168	UUCCCUCCUUCCUUCUGCCCU

5558	169	UGGAACCUUCCAGCCCAGCUG

5559	170	AGAACAAUCUUUACAAACAUU

5560	171	UCUUCUCUUUCUCCCUCCUGG

5561	172	UUCCUUCCUUCUGUUCCUUUG

5562	173	UUAUUAUAAAGACAUAUUUAC

5563	174	UCUACUUUGUGAAACAUAAAA

5564	175	UGCACGUGCAAUAUGUGGGCA

5565	176	UUCCUCCCAUCUUUCUUUCCU

5566	177	AACUCUACUUUGUGAAACAUA

5567	178	UUCUUGUGAGAGAACGGGAAU

5568	179	UCUCUGCAUUCUUCCCUGGAG

5569	180	ACAAUUUCUUAAUGAACAGGG

5570	181	AUAAACAACCACUUUAAAUAA

5571	182	AGGUCUCCAAAGUCAGUCCAG

5572	183	AGAAGCAGACCAAUCUAUGGA

5573	184	AACAAAGUCAUUAUCAAAUGU

5574	185	AUGCUCCACCCACUUCACCAG

5575	186	AAUCAUAAACAACCACUUUAA

5576	187	UGAUUGAAGGCUACCUCGGAC

5577	188	UAAGAAGGCUAAGUGACCUUC

5578	189	CAGAACAAUCUUUACAAACAU

5579	190	AACUGAGCAAACGCUGAUGCU

5580	191	CUCUUAACUAGAGUCUCUCCU

5581	192	ACAACCACUUUAAAUAAGGCA

5582	193	UAUAAAUUAGUAUAAGAAUCA

5583	194	UUUCUCCCUCCUGGGAACCCU

5584	195	UCUCUUUCUCCCUCCUGGGAA

5585	196	UUUGCCUAAGAAGGCUAAGUG

5586	197	UAUUCCUGCUGCACUUCCUCC

5587	198	ACUAGAGUCUCUCCUUGCUUU

5588	199	AAGAAGGGAGGCUUUCUGGGG

5589	200	AUUGGGAGGCACACUAAGGCA

5590	201	UUCUCCCUCCUGGGAACCCUG

5591	202	UGGGUCUGGGAAUGCUGCCAG

5592	203	UCAGGGACCCUCCACACACCG

5593	204	UGAGUGUGCGCGCUGAGCCCC

5594	205	AAGUGACAAAGGACUUCACGG

5595	206	AAUAUCUUUGUAUAAAUUAGU

5596	207	CUCUGCAAUGACUCUGAGCAG

5597	208	CUUUCCUUCCUUCUGUUCCUU

5598	209	AGAUUCAUGCUGCUCCUUGGG

5599	210	CAACAGGACAGUUCACAGCCA

5600	211	UUAGCAGCAGCAUAGGUAAAG

5601	212	AACUGUUUAUUAUAAAGACAU

5602	213	AAGUGACCUUCAAGGGUCCUG

5603	214	UUCCUCCGACCUCCCUGCCAG

5604	215	GUCUUCUCUUUCUCCCUCCUG

5605	216	CUUAACUGAGCAAACGCUGAU

5606	217	UAUUAUAAAGACAUAUUUACA

5607	218	AUUCCCAUCGGGAAGCGGCAU

5608	219	AUCAUAAACAACCACUUUAAA

5609	220	UAUUGGGAGGCACACUAAGGC

5610	221	AAGGCUACCUCGGACUCCUGA

5611	222	GUGAUUGAAGGCUACCUCGGA

5612	223	UCCCAUCUUUCUUUCCUUCCU

5613	224	UCAUAAAGUAGGAGAUGGGAG

5614	225	ACAAAGUCAUUAUCAAAUGUA

5615	226	UGACCUUCAAGGGUCCUGUCA

5616	227	AAAGUUGGGCAUCAGGCUCUU

5617	228	ACUCUGAGCAGGUCACUCCCC

5618	229	AUCUUUGUAUAAAUUAGUAUA

5619	230	UGAUACAAACAAAGUCAUUAU

5620	231	CUUCCUUCUGUUCCUUUGCUU

5621	232	UCCUGGGAGGGUAUAUAGCCA

5622	233	CAACUCUACUUUGUGAAACAU

5623	234	UUUGUAUAAAUUAGUAUAAGA

5624	235	CUUGUCUUCUCUUUCUCCCUC

5625	236	UGGGAUGCAGGCACUUACCUC

5626	237	UCUUCUGCAGCCUCCUCUCCC

5627	238	AUGACCUCCAAGAGUAAGGGC

5628	239	AAUUAGUAUAAGAAUCAUAAA

5629	240	UGGGCAUCAGGCUCUUGUCUU

5630	241	UCUCUACCUCUCCCUUAACUG

5631	242	AUUAUAAAGACAUAUUUACAC

5632	243	UAACUGAGCAAACGCUGAUGC

5633	244	UCAUCAAGAGGGAAGAGGGCG

5634	245	UCUGUUCCUUUGCUUUCUUUU

5635	246	AUCUCCCAGCUUUCUUAGCCA

5636	247	UGCUGGAGCCCACAGAAGGGA

5637	248	UUCUGGGCACCGACCAGUCCC

5638	249	UGGAUAGGCAAACAUUGGGGC

5639	250	UCCGCUCUUCUGCAGCCUCCU

5640	251	UGACCUCCAAGAGUAAGGGCG

5641	252	UAGGUCAGGGAGGUGGGAGCA

5642	253	AAGUUGGGCAUCAGGCUCUUG

5643	254	AUUAGGACACCCAAACAGAUG

5644	255	UUUAAUCAGUAUGUUCUUAAA

5645	256	UUAAUGAACAGGGCCUUAAUA

5646	257	GUCAGCUCUAACAUUCUGUGA

5647	258	CCUGUCAGCUCUAACAUUCUG

5648	259	ACCUCUUAACUAGAGUCUCUC

5649	260	UCAACACGAAGGGAAGGCCAU

5650	261	CUAUGGAGGAGACAUAACCGC

5651	262	UCCAAGAGUAAGGGCGAACUG

5652	263	CUUCUGUUCCCUAUCUCCCAG

5653	264	AAUGACUCUGAGCAGGUCACU

5654	265	ACAAACAAAGUCAUUAUCAAA

5655	266	AUUCCUGCUGCACUUCCUCCC

5656	267	ACCGCGGUCAAGGAGAGCCAG

5657	268	GAAUCAUCCAAACUACAGCCA

5658	269	UACAGCAGGUGCGAGGUGAGA

5659	270	AGGAAGGUCCGGUCAACACGA

5660	271	AUGAUACAAACAAAGUCAUUA

5661	272	CUUUACAAACAUUGAACACAG

5662	273	UCAUGCUGCUCCUUGGGCCGC

5663	274	AGCCCUGGAAGGAAGGUCCGG

5664	275	UGAGAGCUGAAUGGACGUGAG

5665	276	UUAAAUAAACUGCUUUAAAAA

5666	277	ACAUUGCCGUCUUCCAGCCCA

5667	278	AAUCUUUACAAACAUUGAACA

5668	279	AUGACUCUGAGCAGGUCACUC

5669	280	AUUAGAGUACCCUGGGUCUGG

5670	281	AAACGCUGAUGCUCCACCCAC

5671	282	AAGCAGACCAAUCUAUGGAGG

5672	283	UCCUUCCUUCUGCCCUUCCCU

5673	284	CUUUCUUUCCUUCCUUCUGUU

5674	285	UUGACCCUCUGGGCUGCACCA

5675	286	UUCCUUGACCCUCUGGGCUGC

5676	287	AACAGGGCCUUAAUAUCUUUG

5677	288	UUCCCUAUCUCCCAGCUUUCU

5678	289	AUCAUCAAGAGGGAAGAGGGC

5679	290	AUCGGGAAGCGGCAUCAGGGA

5680	291	UGAAUGGACGUGAGGCCUCCA

5681	292	CAUUUAAUCAGUAUGUUCUUA

5682	293	AAGAGACUUUCUGGGCACCGA

5683	294	UGAGACAGGCAGGGACUAGGG

5684	295	AUGGACUGGACGGAUUCUUGU

5685	296	AGAAGGCUAAGUGACCUUCAA

5686	297	AAAGUCAUUAUCAAAUGUAUU

5687	298	UGACCUGGUCAUUAAGCAUAG

5688	299	AGCGUUAGCAGCAGCAUAGGU

5689	300	UAGUAGCGAUCCUGCAUUUAA

5690	301	GAACAAUUUCUUAAUGAACAG

5691	302	AACAUGACCUCCAAGAGUAAG

5692	303	UGAAGGCUACCUCGGACUCCU

5693	304	CUGUCAGCUCUAACAUUCUGU

5694	305	UGUAUAAAUUAGUAUAAGAAU

5695	306	ACACACAAAGUUGGGCAUCAG

5696	307	GAGAGAACGGGAAUCAUCCAA

5697	308	UCCAGUGAUUGAAGGCUACCU

5698	309	UAUCUCAUUCAUCAAGCAACU

5699	310	AGAGUAAGGGCGAACUGUCAG

5700	311	UCCCUCCUUCCUUCUGCCCUU

5701	312	UCCUGCUUCAGAAAGGCAUGG

5702	313	UUUCUGGGCACCGACCAGUCC

5703	314	AGGCACUUCAUUUGCUUUGAA

5704	315	UCUGCCCUUCCCUUCCUUCUU

5705	316	CUAACAUUCUGUGAUUCUUGG

5706	317	UAUCUCCCAGCUUUCUUAGCC

5707	318	CAAGCAACUCUACUUUGUGAA

5708	319	AACCGAUUUGGGAUGCAGGCA

5709	320	AUACAAACAAAGUCAUUAUCA

5710	321	UCCUUCUGCCCUUCCCUUCCU

5711	322	ACAUGAGGAAGGAAGGCCCAA

5712	323	GAAGGGAGCACUUCCACCCCG

5713	324	GUAGUCUCAGUGCCUGAGCCG

5714	325	UCCUGUCAGCUCUAACAUUCU

5715	326	UCCCUAUCUCCCAGCUUUCUU

5716	327	CUAAGAAGGCUAAGUGACCUU

5717	328	AGGACACCCAAACAGAUGCCA

5718	329	AAUCAGUAUGUUCUUAAAUAA

5719	330	AGUUGACCUAGAACCGAUUUG

5720	331	CAAACGCUGAUGCUCCACCCA

5721	332	AGCAGCAGCAUAGGUAAAGGG

5722	333	AACCUUCCAGCCCAGCUGGGG

5723	334	CUGGUCAUUAAGCAUAGGGAU

5724	335	UCAUAAACAACCACUUUAAAU

5725	336	AGAGAAGUGACAAAGGACUUC

5726	337	CAGAGCCGCAGAUUCAUGCUG

5727	338	AAGGGAACAAUUUCUUAAUGA

5728	339	CUAGAGUCUCUCCUUGCUUUU

5729	340	UCAGAAAGGCAUGGGUCCCUU

5730	341	UAGCGAUCCUGCAUUUAAUCA

5731	342	UUCUGUUCCCUAUCUCCCAGC

5732	343	UGGAGUCCAGUGAUUGAAGGC

5733	344	AGUCAUUAUCAAAUGUAUUUA

5734	345	GAAUCAUAAACAACCACUUUA

5735	346	AGGUCCGGUCAACACGAAGGG

5736	347	AGUUAUGGAACCUUCCAGCCC

5737	348	GAGAGGGUGCUAUUCCUGCUG

5738	349	AGGAAGAAGGGAGUAUUGGGA

5739	350	CUCUAACAUUCUGUGAUUCUU

5740	351	AGAAGUGACAAAGGACUUCAC

5741	352	UCAGGGAGGUGGGAGCAGCUC

5742	353	AGGAGACACAGAAAGGAAGGG

5743	354	UGCACUUCCUCCCAUCUUUCU

5744	355	AUUGAAGGCUACCUCGGACUC

5745	356	AGAAGGGAGCACUUCCACCCC

5746	357	UCCCUUAUGGGAGAGGCGGGG

5747	358	UGACAAAGGACUUCACGGGCC

5748	359	UGCAAUAUGUGGGCAUGGGGA

5749	360	ACAGGCAGGGACUAGGGCGGA

5750	361	ACUGAGCAAACGCUGAUGCUC

5751	362	UGCGAGGUGAGAGCUGAAUGG

5752	363	ACCUCUCCCUUAACUGAGCAA

5753	364	UGCUCCACCCACUUCACCAGA

5754	365	CUUCUGUUCCUUUGCUUUCUU

5755	366	UCAUUAUCAAAUGUAUUUAUU

5756	367	UGACUCUGAGCAGGUCACUCC

5757	368	AAGGAAGGUCCGGUCAACACG

5758	369	AGUAGGAGAUGGGAGACCUGG

5759	370	UGGUCAUUAAGCAUAGGGAUU

5760	371	GAGCGGUAGUCUCAGUGCCUG

5761	372	UAAUGAACAGGGCCUUAAUAU

5762	373	UCCCUGCACGUGCAAUAUGUG

5763	374	AGCACCUCUUAACUAGAGUCU

5764	375	ACAAAGUUGGGCAUCAGGCUC

5765	376	CAGAGAAGCAGACCAAUCUAU

5766	377	AUGGACGUGAGGCCUCCAGAG

5767	378	AUCAGUAUGUUCUUAAAUAAA

5768	379	AGCGAUCCUGCAUUUAAUCAG

5769	380	UGAGGCAGGAGACACAGAAAG

5770	381	AAGAGUAAGGGCGAACUGUCA

5771	382	UUGCCUCUCCCUUCCCUUCCC

5772	383	CUUCUCUUUCUCCCUCCUGGG

5773	384	CUCAUUCAUCAAGCAACUCUA

5774	385	AGGCAGGAGACACAGAAAGGA

5775	386	UUAGUAUAAGAAUCAUAAACA

5776	387	UUACCUCCCUGCACGUGCAAU

5777	388	AAGCAACUCUACUUUGUGAAA

5778	389	ACCUCCAAGAGUAAGGGCGAA

5779	390	UAAUCAGUAUGUUCUUAAAUA

5780	391	AGUCCUGCUUCAGAAAGGCAU

5781	392	AGGCAGGUGAGAAGAGCUGGG

5782	393	GUGGAUAGGCAAACAUUGGGG

5783	394	GGAUUCUUGUGAGAGAACGGG

5784	395	UCUCAGUGCCUGAGCCGCCCC

5785	396	ACUGUUUAUUAUAAAGACAUA

5786	397	UCCUGCAUUUAAUCAGUAUGU

5787	398	UUCAGUCCUGCUUCAGAAAGG

5788	399	AUUUAAUCAGUAUGUUCUUAA

5789	400	AUUAGUAUAAGAAUCAUAAAC

5790	401	AUAAAGUAGGAGAUGGGAGAC

5791	402	CAAGCAUGAGCCUUUAAGCAG

5792	403	GACAUAUUUACACAGAACAAU

5793	404	UAGAUGAGACAGGCAGGGACU

5794	405	UGUUCCCUAUCUCCCAGCUUU

5795	406	AGCAGGAGCGCCUGCACGCAG

5796	407	UUAGGACACCCAAACAGAUGC

5797	408	UCUUAAAUAAACUGCUUUAAA

5798	409	UCCUUCUGUUCCUUUGCUUUC

5799	410	CCCAUCUUUCUUUCCUUCCUU

5800	411	AAGUCAUUAUCAAAUGUAUUU

5801	412	UUCUUUCCUUCCUUCUGUUCC

5802	413	AUGGAGUCCAGUGAUUGAAGG

5803	414	ACGGAAGCUAGGGCCUCCCGG

5804	415	UACCCUGGGUCUGGGAAUGCU

5805	416	ACAAGGGAUCUGCUGGAGCCC

5806	417	AGAUGGACUGGACGGAUUCUU

5807	418	AUCAAGAGGGAAGAGGGCGUC

5808	419	ACCUGGAGCUUGGGCUAGCUG

5809	420	UCUUAAUGAACAGGGCCUUAA

5810	421	GAUUCUUGUGAGAGAACGGGA

5811	422	AUUGCCGUCUUCCAGCCCAUU

5812	423	AUUAUCAAAUGUAUUUAUUGC

5813	424	AGACAGGCAGGGACUAGGGCG

5814	425	UGCAUUUAAUCAGUAUGUUCU

5815	426	CGCAGAUUCAUGCUGCUCCUU

5816	427	AUUAAGCAUAGGGAUUCAUUU

5817	428	AUUCAUGCUGCUCCUUGGGCC

5818	429	CACCUCUUAACUAGAGUCUCU

5819	430	AACAACCACUUUAAAUAAGGC

5820	431	UCCAAAGUCAGUCCAGGGAGG

5821	432	AGAUGAGACAGGCAGGGACUA

5822	433	GCUAUCUCAUUCAUCAAGCAA

5823	434	AACGGGAAUCAUCCAAACUAC

5824	435	ACUACCCUCUUCUGUUCCCUA

5825	436	AAGAAGGCUAAGUGACCUUCA

5826	437	UCUGUUCCCUAUCUCCCAGCU

5827	438	AGGUGAGAGCUGAAUGGACGU

5828	439	AGGGACCCUCCACACACCGCG

5829	440	CUGAACAUGACCUCCAAGAGU

5830	441	AGUAUUGGGAGGCACACUAAG

5831	442	AGGCUCUUGUCUUCUCUUUCU

5832	443	UGCAUUCUUCCCUGGAGGCCA

5833	444	CACUUCACCAGAGCUCCUGAA

5834	445	CAUCAGGCUCUUGUCUUCUCU

5835	446	GUUAUGGAACCUUCCAGCCCA

5836	447	CAGCAGCAGCAGCAGCAGCAG

5837	448	CUUACCUCCCUGCACGUGCAA

5838	449	GGAGGAGACAUAACCGCCGGG

5839	450	GUAAGGGCGAACUGUCAGCUU

5840	451	CUGACCUGGAGCUUGGGCUAG

5841	452	AGGUGGAUAGGCAAACAUUGG

5842	453	CUCUUGUCUUCUCUUUCUCCC

5843	454	CAUAUUUACACAGAACAAUCU

5844	455	AAGGGCGAACUGUCAGCUUUU

5845	456	AGACUUUCUGGGCACCGACCA

5846	457	AAACAAAGUCAUUAUCAAAUG

5847	458	ACACUAAGGCAAGAGAAGUGA

5848	459	UCCUUGACCCUCUGGGCUGCA

5849	460	CAAUUUCUUAAUGAACAGGGC

5850	461	CAUCAAGCAACUCUACUUUGU

5851	462	AGAAGAAGGGAGGCUUUCUGG

5852	463	CAGCAGCAGCAGCAGCAGCGU

5853	464	GAACAAUCUUUACAAACAUUG

5854	465	AGGCUAAGUGACCUUCAAGGG

5855	466	UCGGGAAGCGGCAUCAGGGAC

5856	467	UAGCAGCAGCAUAGGUAAAGG

5857	468	AAGGCAUGGGUCCCUUAUGGG

5858	469	UCUGCAGCCUCCUCUCCCGCC

5859	470	GAAGCAGACCAAUCUAUGGAG

5860	471	AUGAGCCUUUAAGCAGCAGCA

5861	472	AGCUGAAUGGACGUGAGGCCU

5862	473	GAAGGCUACCUCGGACUCCUG

5863	474	CUGUUCCCUAUCUCCCAGCUU

5864	475	AGCUCUAACAUUCUGUGAUUC

5865	476	AGCAGCGUUAGCAGCAGCAUA

5866	477	UCUGGGCACCGACCAGUCCCC

5867	478	AGGAAGAUGGACUGGACGGAU

5868	479	ACCUGGUCAUUAAGCAUAGGG

5869	480	GAUGCAGGCACUUACCUCCCU

5870	481	AUCUGCUGGAGCCCACAGAAG

5871	482	CUAUUCCUGCUGCACUUCCUC

5872	483	AUCCUGCAUUUAAUCAGUAUG

5873	484	CAGAAGACACCCACCAAGGAU

5874	485	ACAACAGGACAGUUCACAGCC

5875	486	UGCAGCCUCCUCUCCCGCCGC

5876	487	UCAGUCCUGCUUCAGAAAGGC

5877	488	ACGCUGAUGCUCCACCCACUU

5878	489	CAGCAGCAGCGUUAGCAGCAG

5879	490	GAACCUUCCAGCCCAGCUGGG

5880	491	UAUGGAACCUUCCAGCCCAGC

5881	492	AAAUUAGUAUAAGAAUCAUAA

5882	493	CUCCUGAACAUGACCUCCAAG

5883	494	UCCUGACCUGGAGCUUGGGCU

5884	495	CUGUUUAUUAUAAAGACAUAU

5885	496	GCGGACAUUGCCGUCUUCCAG

5886	497	CUCUGAGCAGGUCACUCCCCU

5887	498	CACACACACAAAGUUGGGCAU

5888	499	CCAGAGAAGCAGACCAAUCUA

5889	500	AUGUGACCUGGUCAUUAAGCA

5890	501	AGGAAGGCCCAAAUGAAGGUU

5891	502	UCUCCCUUAACUGAGCAAACG

5892	503	AGCGGUAGUCUCAGUGCCUGA

5893	504	UCUGCAUUCUUCCCUGGAGGC

5894	505	UCCACCCACUUCACCAGAGCU

5895	506	UACUCCUGGGAGGGUAUAUAG

5896	507	CAGUGAUUGAAGGCUACCUCG

5897	508	GACUUUCUGGGCACCGACCAG

5898	509	CUUUGUAUAAAUUAGUAUAAG

5899	510	AUGAACAGGGCCUUAAUAUCU

5900	511	ACCCACUUCACCAGAGCUCCU

5901	512	CUUCUGCAGCCUCCUCUCCCG

5902	513	AAGAUGGACUGGACGGAUUCU

5903	514	UGUGCCCUGUCUGGAUCCCCG

5904	515	AGGCACACUAAGGCAAGAGAA

5905	516	AGUAUAAGAAUCAUAAACAAC

5906	517	UGCGGGCGCAGAGCUCGGGAG

5907	518	AUGUGCCCUGUCUGGAUCCCC

5908	519	AAGAGCUGGGCCCACUGGUGG

5909	520	AGCGCCUGCACGCAGAGCCGC

5910	521	UAAAGUAGGAGAUGGGAGACC

5911	522	AUUUCCUCCGACCUCCCUGCC

5912	523	GACAUUGCCGUCUUCCAGCCC

5913	524	AAAGAAGGCCCAAUCCCUGAU

5914	525	AUGCUGCUCCUUGGGCCGCCG

5915	526	AGGAGACAUAACCGCCGGGGG

5916	527	AAGACAUAUUUACACAGAACA

5917	528	UCCGGGAGCGGCAGCGGCGAG

5918	529	AGAUGGGAGACCUGGUCCCCA

5919	530	UGCCUCUCCCUUCCCUUCCCC

5920	531	AAGAAGGGAGUAUUGGGAGGC

5921	532	CUGGAAGGAAGGUCCGGUCAA

5922	533	GAACAGGGCCUUAAUAUCUUU

5923	534	CCCACUUCACCAGAGCUCCUG

5924	535	AAAGACAUAUUUACACAGAAC

5925	536	GAAUUUCCUCCGACCUCCCUG

5926	537	UGGACGGAUUCUUGUGAGAGA

5927	538	AGGGCAGACAUGAGGAAGGAA

5928	539	GAGGAGACAUAACCGCCGGGG

5929	540	UGCUUCAGAAAGGCAUGGGUC

5930	541	CAAGGGUCCUGUCAGCUCUAA

5931	542	UCUUGUGAGAGAACGGGAAUC

5932	543	AGCAGACCAAUCUAUGGAGGA

5933	544	GAGUCCAGUGAUUGAAGGCUA

5934	545	AGGUGAGAAGAGCUGGGCCCA

5935	546	UCCAGCCCAUUCCCAUCGGGA

5936	547	AGGCGUUUGCCUAAGAAGGCU

5937	548	CCCUUAACUGAGCAAACGCUG

5938	549	CGGCUCUGCAAUGACUCUGAG

5939	550	AGGGAACAAUUUCUUAAUGAA

5940	551	UCCCGGCUCUGCAAUGACUCU

5941	552	CUGGGAACCCUGCUCAAGCAA

5942	553	AGGGCCUUAAUAUCUUUGUAU

5943	554	AGCAUGAGCCUUUAAGCAGCA

5944	555	UGAGAAGAGCUGGGCCCACUG

5945	556	AGUAAGGGCGAACUGUCAGCU

5946	557	AACCACUUUAAAUAAGGCAGC

5947	558	AGGUCAGGGAGGUGGGAGCAG

5948	559	UGCCUAAGAAGGCUAAGUGAC

5949	560	CCACACACCGCGGUCAAGGAG

5950	561	CAGCUCUAACAUUCUGUGAUU

5951	562	UGGGAGGCACACUAAGGCAAG

5952	563	GGUGAGAGCUGAAUGGACGUG

5953	564	GAGGGCGUCAUAAAGUAGGAG

5954	565	AGCUUGCCUCUCCCUUCCCUU

5955	566	UCUUCCCUCCUUCCUUCUGCC

5956	567	AGAAGAGCUGGGCCCACUGGU

5957	568	GGAAGGUCCGGUCAACACGAA

5958	569	CAUUCCUUGACCCUCUGGGCU

5959	570	AUGAGGCAGGAGACACAGAAA

5960	571	GCAUUUAAUCAGUAUGUUCUU

5961	572	CUUCCCUUCCUUCUUCUCCCC

5962	573	CACUACCCUCUUCUGUUCCCU

5963	574	GACAUGAGGAAGGAAGGCCCA

5964	575	UGAUGCUCCACCCACUUCACC

5965	576	AAAGUAGGAGAUGGGAGACCU

5966	577	CACAGAAGGGAGCACUUCCAC

TABLE 9

Results for KIF20A. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_
NO	id	AS Sequence

5967	1	UAAUUUAGCUUUAACCUCCUG

5968	2	UUCACAUUGACAAUCAUGCAG

5969	3	UUUGAGUACAUCCUUUACCAU

5970	4	UUCUUGUCCACAUCAAUGGUG

5971	5	UUGACAAUCAUGCAGGAACGG

5972	6	UAGCUCUGCUUUGCACUGCUG

5973	7	UAGGUCAUAAAGCAGUUCGUU

5974	8	AACUACGACAUCGUCAUCGGA

5975	9	UACCUGAAGACUAUGUUCCUU

5976	10	UUGAUGGUACCUUGAAUCGUG

5977	11	UUUCCUGCUUCCUUCAACCGU

5978	12	UAAGAUGUCAUCACAAGUGGU

5979	13	UUACUCACACCUAGUCGCCGA

5980	14	UUGCACAUGAAUCCAGUUGAG

5981	15	UUCGAUGUAGACACUCCUCUU

5982	16	UCUGAUAGCAGGUUCUUGCGU

5983	17	UUCACCACUCUUCUGAUCUUU

5984	18	UCGAUGACUUGUUUCAUCCAG

5985	19	UUUAACCUCCUGAAGCUGCUG

5986	20	UUGUAGAUCUCAAAGAAUGAG

5987	21	UUGAGAUCUUUCACAUAGGGA

5988	22	AAUAUCUUUAAUAUAACUGUU

5989	23	UACGACAUCGUCAUCGGACAG

5990	24	UUCUAAUAGGUCAUAAAGCAG

5991	25	UUUCAACACAGUAUGAUACUG

5992	26	AUGACUUGUUUCAUCCAGCUG

5993	27	UGGAACACUCGAGUCAACUUG

5994	28	UACAUCCUUUACCAUCUCCUU

5995	29	AUCUGCUUGCUGUCUAGCCAG

5996	30	AACACUCGAGUCAACUUGCUG

5997	31	UUCACUGCACCACUGUUCCCG

5998	32	UUAUGCAACUCUUCAGUGGUA

5999	33	UUGGAGGCUAUUGAAGAUCAG

6000	34	UUCAGGAGAGUAGCUGACCCA

6001	35	UAUAAUUCCUGAUAUAUGGUA

6002	36	UUGAUUAAGAUGUCAUCACAA

6003	37	UCACAGAGUGACAGCUCGCUG

6004	38	UUCCACAACUUGUAGGAGCUC

6005	39	UUGUAGAACAAGGGUCUCCAC

6006	40	UUUCACUAGCACCAUGUUGUU

6007	41	UUUACCAUCUCCUUCACAGUU

6008	42	UGUUCUACCAUCUCAUUGCAA

6009	43	UAAUAUCUUUAAUAUAACUGU

6010	44	UUGUCCUCUAGGGAGGUAGAG

6011	45	UUUCUGAAGCUCUGUCCGCAA

6012	46	UUCUUCAUUUCCUCCUGUCGG

6013	47	AUCUCGGAGAUGCAUCUCCAG

6014	48	UACUUAUGCAACUCUUCAGUG

6015	49	UAGCACCAUGUUGUUCUGCAG

6016	50	AUACAUGCUGCCUUCUUCCGA

6017	51	UUAGGUUGAAGAAGGAUGCCU

6018	52	UCUGAUACUUAUGCAACUCUU

6019	53	UUAAGAUGUCAUCACAAGUGG

6020	54	UGCACUGCUGUAAUUUAGCUU

6021	55	UAUACUUUCACCUUCUCCAUA

6022	56	UUUCGAUGUAGACACUCCUCU

6023	57	UUUAGCUCUGCUUUGCACUGC

6024	58	UCGGAGAUGCAUCUCCAGCUG

6025	59	UACUGCUGGUACACUGACUGA

6026	60	UUCGUUGUAGAUCUCAAAGAA

6027	61	UAGAACAAGGGUCUCCACAUU

6028	62	UUCAUCUCGGAGAUGCAUCUC

6029	63	UAACUUCUUGUCCACAUCAAU

6030	64	UUCAGUGGUAGAGUUUAGCUC

6031	65	UCUCAAUACGGACACAACCCU

6032	66	UAGCAGGGACAGCUUCUUCAU

6033	67	UGUCUGAGUAUUGCAUCCUGG

6034	68	AUUUCUUCAGGAGAGUAGCUG

6035	69	AUCCUGAUUGAGAAGAUGCUG

6036	70	UUCUGGUUGAGGUGGGUGCUG

6037	71	UUGUCAGUGACUCCUUGAGGA

6038	72	UUCCUGUCGUUCCAACUCUGA

6039	73	UGACAGCUCGCUGAUCUUGGG

6040	74	UCUGAAGGUAACAAGGGCCUA

6041	75	UAUCUUUAAUAUAACUGUUUU

6042	76	UUAACCUCCUGAAGCUGCUGG

6043	77	UGUCGUUCCAACUCUGAAGGU

6044	78	UAGACACUCCUCUUCAAGGAA

6045	79	UUCCUUGAUGAACGAGUGCAG

6046	80	AUAUCUUUAAUAUAACUGUUU

6047	81	AUCUCAAAGAAUGAGAUCCAG

6048	82	UUUAGCUUUAACCUCCUGAAG

6049	83	UAACCUCCUGAAGCUGCUGGG

6050	84	UACUCACACCUAGUCGCCGAA

6051	85	UUGCAUCUGUUCUACCAUCUC

6052	86	UUCCUGCUUCCUUCAACCGUU

6053	87	UGACUGAUAGAAGAGAGCCCA

6054	88	UCUUCAUUUCCUCCUGUCGGA

6055	89	UAGUCGCCGAAGCUGGACUUU

6056	90	UUGAUGAACGAGUGCAGGGAU

6057	91	UUUCAUCAUAGGUAGAUGCAC

6058	92	UAGGUUGAAGAAGGAUGCCUG

6059	93	UGACUUGUUUCAUCCAGCUGG

6060	94	UUCACUAGCACCAUGUUGUUC

6061	95	UCUUCUGAUCUUUGCAGCGCU

6062	96	UGGUAGAGUUUAGCUCUGCUU

6063	97	UCUGAGUAUUGCAUCCUGGAU

6064	98	AUAAUAUCUUUAAUAUAACUG

6065	99	UAGCAGGUUCUUGCGUACCAC

6066	100	UUCCUCCUGUCGGAUCUGCUU

6067	101	UUAGCUCUGCUUUGCACUGCU

6068	102	AACCCUGAUCUUCCUGUCGUU

6069	103	UAGGCGGUUCUAAUAGGUCAU

6070	104	UCAUCGGACAGCAAGCCCGCU

6071	105	AUUCACAUUGACAAUCAUGCA

6072	106	UAAAUUUCGAAGGAAUGGUUU

6073	107	UCUUGCACAUGAAUCCAGUUG

6074	108	UUGGAGGCCUCCAUUUAGCAG

6075	109	UCCUGUCGGAUCUGCUUGCUG

6076	110	UUGGAGAGACUCACCAAGUUU

6077	111	UCGAUGUAGACACUCCUCUUC

6078	112	UUGCACUGCUGUAAUUUAGCU

6079	113	AAGCUCUCUCUGCUGAUUGGA

6080	114	UACAUGCUGCCUUCUUCCGAA

6081	115	UACUGCUCAGCAAUACAUGCU

6082	116	AUUGAGAAGAUGCUGUGACUG

6083	117	AACUUGUAGGAGCUCCUCUUU

6084	118	UAGAGACGACAGAGCAGUCUG

6085	119	UAAUAGGUCAUAAAGCAGUUC

6086	120	UUGGAGUUUCAACACAGUAUG

6087	121	UUACCAUCUCCUUCACAGUUA

6088	122	UCCAUAUGUAUAGAUGAGCCA

6089	123	UGCAUCUGUUCUACCAUCUCA

6090	124	AUCACAGAGUGACAGCUCGCU

6091	125	UGCUUGUAGAACAAGGGUCUC

6092	126	UUCUUGCGUACCACAGACCCC

6093	127	UAGCCGCAAAGUCUGCCUCUU

6094	128	UUUGUGACCGCCGUAGGGCCA

6095	129	AUGCAUCUCCAGCUGUAGCUU

6096	130	AGCUCUGUCCGCAACAGCCUU

6097	131	UUUGCCGGGACAGGUAGUGGG

6098	132	UACGGACACAACCCUGAUCUU

6099	133	UCUUCCUGUCGUUCCAACUCU

6100	134	UGUUGUUCUGCAGUUCAGCCA

6101	135	UACACUGACUGAUAGAAGAGA

6102	136	AAGAAUGAGAUCCAGAUGGAG

6103	137	AACAGCCUUAUAUUCUUCUGG

6104	138	UCAUAGGUAGAUGCACAGGGA

6105	139	UCUUGCGUACCACAGACCCCA

6106	140	AUCUUUAAUAUAACUGUUUUU

6107	141	UUCUGAUCUUUGCAGCGCUCU

6108	142	AGAAACCUUGGAACACUCGAG

6109	143	UUGGAACACUCGAGUCAACUU

6110	144	AUUGCAAAUUUCAUCUCGGAG

6111	145	UGUAGGAGCUCCUCUUUGCCA

6112	146	UGCAUCUCCAGCUGUAGCUUU

6113	147	UUCUUCAGGAGAGUAGCUGAC

6114	148	UCACCUUCUCCAUACUGUCCU

6115	149	UUAGUGACUCCAUAUGUAUAG

6116	150	UGAAGAAGGAUGCCUGUCCCA

6117	151	AAUUUCAUCUCGGAGAUGCAU

6118	152	AAGCUCUGUCCGCAACAGCCU

6119	153	UCUCAUUGCAAAUUUCAUCUC

6120	154	UCAUUGCAAAUUUCAUCUCGG

6121	155	UUGCCGGGACAGGUAGUGGGG

6122	156	UCGGAUCUGCUUGCUGUCUAG

6123	157	ACAUUGACAAUCAUGCAGGAA

6124	158	UAUGCAACUCUUCAGUGGUAG

6125	159	UACCUCAUUGGAGAGCAAGGG

6126	160	AAGUUUCUGAAGCUCUGUCCG

6127	161	AAGAAACCUUGGAACACUCGA

6128	162	UAUUUCUUCAGGAGAGUAGCU

6129	163	AUGUGAACAAUAAUAUCUUUA

6130	164	UGAUAGAAGAGAGCCCAGCAA

6131	165	UCUAACUUCUUGUCCACAUCA

6132	166	AAUAUCAUCAUCAAGGCCUGU

6133	167	UCUGAUCUUUGCAGCGCUCUG

6134	168	UCUUCUAACUUCUUGUCCACA

6135	169	UGGUACCUUGAAUCGUGUGGG

6136	170	UUUCUUCAGGAGAGUAGCUGA

6137	171	ACACAGUAUGAUACUGCUCAG

6138	172	UUUAGCAGGGACAGCUUCUUC

6139	173	UAGCUUUAACCUCCUGAAGCU

6140	174	AUCUGUUCUACCAUCUCAUUG

6141	175	AUCGAUGACUUGUUUCAUCCA

6142	176	UGAUCUUUGCAGCGCUCUGAG

6143	177	UCCUCCUGUCGGAUCUGCUUG

6144	178	UUUGAUUAAGAUGUCAUCACA

6145	179	AUGAAUCCAGUUGAGAUCUUU

6146	180	AGCUUCUAGCUCUUCAAUCUU

6147	181	UUGUAGGAGCUCCUCUUUGCC

6148	182	AUCUCCUUCACAGUUAGGUUG

6149	183	UGUCAGUGACUCCUUGAGGAU

6150	184	UUCUCCAUACUGUCCUCAGAU

6151	185	AUCUUGCACAUGAAUCCAGUU

6152	186	AGCAUCUUGCACAUGAAUCCA

6153	187	UUCACAGUUAGGUUGAAGAAG

6154	188	AGUGACAGCUCGCUGAUCUUG

6155	189	UAACAAGGGCCUAACCCUCAA

6156	190	UAGAGUUUAGCUCUGCUUUGC

6157	191	AUGAAGAGUUUCAUCAUAGGU

6158	192	ACUGCUGGUACACUGACUGAU

6159	193	UGCUGCUUGUCCUCUAGGGAG

6160	194	UCAUCAUAGGUAGAUGCACAG

6161	195	UUGAGUACAUCCUUUACCAUC

6162	196	UGGACUUUCGCAGCCGCAGAG

6163	197	AACUCUGAAGGUAACAAGGGC

6164	198	UGAGAAGAUGCUGUGACUGCG

6165	199	UGCAACUCUUCAGUGGUAGAG

6166	200	UUGUCCACAUCAAUGGUGAAG

6167	201	ACCAGGUUCUGCUUUGACCGG

6168	202	AUAGGUCAUAAAGCAGUUCGU

6169	203	UUAGCAGGGACAGCUUCUUCA

6170	204	UUCAACACAGUAUGAUACUGC

6171	205	AAGUGGUCAAGGCUUGACGAA

6172	206	CUAACUUCUUGUCCACAUCAA

6173	207	AGCUUUAACCUCCUGAAGCUG

6174	208	UAGAUGCACAGGGAUUCACAU

6175	209	AUUAAGAUGUCAUCACAAGUG

6176	210	UGGUUGUUGGUUUGGUUGCUG

6177	211	UAAGGGCUGCAGUCUGUUGAG

6178	212	AUACCUGAAGACUAUGUUCCU

6179	213	UGAAGAGUUUCAUCAUAGGUA

6180	214	AAGACUAUGUUCCUUGAUGAA

6181	215	UGCUUUGACCGGUUCUGCUGG

6182	216	UGGAGUUUCAACACAGUAUGA

6183	217	UCAUAAAGCAGUUCGUUGUAG

6184	218	ACUUUCGAUGUAGACACUCCU

6185	219	AUCAUAGGUAGAUGCACAGGG

6186	220	UCCAGUUUCACUAGCACCAUG

6187	221	AAACAUGGGAGAAACUACGAC

6188	222	AACCUUGGAACACUCGAGUCA

6189	223	AACAACAUGAGAUUACAUAGG

6190	224	UGCCUUCUUCCGAAGGUCCAG

6191	225	UUUCGCAGCCGCAGAGCACAA

6192	226	AUACUUAUGCAACUCUUCAGU

6193	227	UCCUGAUAUAUGGUAAAGCAU

6194	228	AAUGUUUCCUGCUUCCUUCAA

6195	229	UGGAACCUGCUGCUUGUCCUC

6196	230	AAACCUUGGAACACUCGAGUC

6197	231	AACAUGAGAUUACAUAGGUGG

6198	232	AUGACUGCUCUUCUCUUUCCC

6199	233	AGGUGUAGGAUCCUGAUUGAG

6200	234	UCAAGGAAGUGGACAGCUCCU

6201	235	UUAAUGUUUCCUGCUUCCUUC

6202	236	CAACAUGAGAUUACAUAGGUG

6203	237	AAGCAGUUCGUUGUAGAUCUC

6204	238	UGAGAUCUUUCACAUAGGGAU

6205	239	UGAAGGUGUAGGAUCCUGAUU

6206	240	AACAAUAAUAUCUUUAAUAUA

6207	241	AUUUAGCAGGGACAGCUUCUU

6208	242	UUGAAGAAGGAUGCCUGUCCC

6209	243	UACAUGGAGAUGUCAGCUUCA

6210	244	AUAUAAUUCCUGAUAUAUGGU

6211	245	UGCAAGAGAGCUUCUAGCUCU

6212	246	UAACCCUCAAGUAUACUUUCA

6213	247	CUGAUCUUCCUGUCGUUCCAA

6214	248	UGCAGCUGUGGACUCAAACAU

6215	249	UAGGGAGGUAGAGACGACAGA

6216	250	AAAUGUUCACUGCACCACUGU

6217	251	UUGUGACCGCCGUAGGGCCAA

6218	252	UCCAUUUAGCAGGGACAGCUU

6219	253	UCCAGUUGAGAUCUUUCACAU

6220	254	UGAUGGUACCUUGAAUCGUGU

6221	255	UUGACCGGUUCUGCUGGUUUU

6222	256	ACAACAUGAGAUUACAUAGGU

6223	257	UGGACAGCUCCUCCUCUUGGA

6224	258	AGUGUCUGAGUAUUGCAUCCU

6225	259	UCCUGUCGUUCCAACUCUGAA

6226	260	UGUCGGAUCUGCUUGCUGUCU

6227	261	UACCAUCUCCUUCACAGUUAG

6228	262	UGCCCUUUGAGUACAUCCUUU

6229	263	AAUACAUGCUGCCUUCUUCCG

6230	264	UCUUUGCAGCGCUCUGAGCCA

6231	265	UCACAUUGACAAUCAUGCAGG

6232	266	UCAACACAGUAUGAUACUGCU

6233	267	AAGUGGACAGCUCCUCCUCUU

6234	268	UUUCACCUUCUCCAUACUGUC

6235	269	UGCUGGUACCUAUCCGACUUU

6236	270	UCGGCCUGUGAAGAAACCUUG

6237	271	UAAUGUUUCCUGCUUCCUUCA

6238	272	AACAAGGGUCUCCACAUUCUC

6239	273	AUCCUGGAUAUAAUUCCUGAU

6240	274	AAUCCCUCCAUCCUUGAUGGU

6241	275	CUUGAUGGUACCUUGAAUCGU

6242	276	AAAGUCUGCCUCUUGCGCUGU

6243	277	UCAGAUGGAACCUGCUGCUUG

6244	278	AACCGUUCACCACUCUUCUGA

6245	279	UUUCCUCCAAUAGUUCCUUUU

6246	280	UGCACCACUGUUCCCGCUGUU

6247	281	AAUGUUCACUGCACCACUGUU

6248	282	UGCAGGAACGGCCUCGGCCUG

6249	283	AAUUUAGCUUUAACCUCCUGA

6250	284	CUUACUCACACCUAGUCGCCG

6251	285	CUAUGUUCCUUGAUGAACGAG

6252	286	UUGUUGGUUUGGUUGCUGAUU

6253	287	AGUUUCACUAGCACCAUGUUG

6254	288	UCGUCAUCGGACAGCAAGCCC

6255	289	UUCUAACUUCUUGUCCACAUC

6256	290	UCUGCUUUGACCGGUUCUGCU

6257	291	UGAUUGGAGAGACUCACCAAG

6258	292	UCAGUGGUAGAGUUUAGCUCU

6259	293	UCAAUAUCAUCAUCAAGGCCU

6260	294	CUCAAUACGGACACAACCCUG

6261	295	UGAGUUAGUGACUCCAUAUGU

6262	296	UGGAGUUCUGGUUGAGGUGGG

6263	297	ACAACUUGUAGGAGCUCCUCU

6264	298	UACUGUCCUCAGAUGGAACCU

6265	299	AAAUCUGCAGCUGUGGACUCA

6266	300	CUUCUUGUCCACAUCAAUGGU

6267	301	UGCUUGUCCUCUAGGGAGGUA

6268	302	UCUAAUAGGUCAUAAAGCAGU

6269	303	UGCAUAGAAAUCAUAUAAGUA

6270	304	AGUUUCUGAAGCUCUGUCCGC

6271	305	ACAGAGUGACAGCUCGCUGAU

6272	306	UGAUACUGCUCAGCAAUACAU

6273	307	ACACUCGAGUCAACUUGCUGU

6274	308	UGAUACUUAUGCAACUCUUCA

6275	309	CAACCGUUCACCACUCUUCUG

6276	310	UCCUUGAGGAUAUUUAGUUUU

6277	311	UUCUAGCUCUUCAAUCUUUUC

6278	312	GUGUCUGAGUAUUGCAUCCUG

6279	313	ACUUAUGCAACUCUUCAGUGG

6280	314	CUUCCUGUCGUUCCAACUCUG

6281	315	ACUUGUAGGAGCUCCUCUUUG

6282	316	UAUCCGACUUUCGAUGUAGAC

6283	317	AAACUACGACAUCGUCAUCGG

6284	318	ACUGCUCAGCAAUACAUGCUG

6285	319	AUUCAGACCCUGAUUGCUGAU

6286	320	UGUAAUUUAGCUUUAACCUCC

6287	321	UCCUGUUUGAUUAAGAUGUCA

6288	322	UCGCAUAGCCGCAAAGUCUGC

6289	323	UGGGUGCUUGUAGAACAAGGG

6290	324	AACUCUUCAGUGGUAGAGUUU

6291	325	AUUGGAGAGACUCACCAAGUU

6292	326	AUUUCCUCCAAUAGUUCCUUU

6293	327	UUCUGCUUUGACCGGUUCUGC

6294	328	UCCAACUCUGAAGGUAACAAG

6295	329	UGACUGCUCUUCUCUUUCCCC

6296	330	UUUCCUCCUGUCGGAUCUGCU

6297	331	GACACAACCCUGAUCUUCCUG

6298	332	UUGCAAAUUUCAUCUCGGAGA

6299	333	AUGUAGACACUCCUCUUCAAG

6300	334	AAGGGAACCAGGUUCUGCUUU

6301	335	UUCAUUGCUCUUCAGGGCAAA

6302	336	AAGUCUGCCUCUUGCGCUGUU

6303	337	AAUCCCAGUUGCAUAGGUGGG

6304	338	ACUAUGUUCCUUGAUGAACGA

6305	339	ACAGUUAGGUUGAAGAAGGAU

6306	340	UUCCUGCAAGAGAGCUUCUAG

6307	341	UGUAGGAUCCUGAUUGAGAAG

6308	342	UUCCAACUCUGAAGGUAACAA

6309	343	UAGGAUCCUGAUUGAGAAGAU

6310	344	AUCAGGUGUUGGAUGAAGUUG

6311	345	AACACAGUAUGAUACUGCUCA

6312	346	UCCUUGAUGAACGAGUGCAGG

6313	347	UAGAUCUCAAAGAAUGAGAUC

6314	348	ACUGUCCUCAGAUGGAACCUG

6315	349	ACCUUGGAACACUCGAGUCAA

6316	350	AACCUCCUGAAGCUGCUGGGU

6317	351	UCUGGUUCUUACGACCCACUU

6318	352	UCAAUACGGACACAACCCUGA

6319	353	UACCUUGAAUCGUGUGGGUUU

6320	354	GAUACUUAUGCAACUCUUCAG

6321	355	UAGUGUCUGAGUAUUGCAUCC

6322	356	UCGUUGUAGAUCUCAAAGAAU

6323	357	AACCUGCUGCUUGUCCUCUAG

6324	358	AUCCCAGUUGCAUAGGUGGGG

6325	359	AGAGCAGUCUGAUAGCAGGUU

6326	360	UGUAGAGAGGUGUUAAUGUUU

6327	361	UCUCCACAUUCUCAAUACGGA

6328	362	UCCCUGAGUUAGUGACUCCAU

6329	363	AUCACAAGUGGUCAAGGCUUG

6330	364	ACUUUCACCUUCUCCAUACUG

6331	365	CUUUGCAGCGCUCUGAGCCAG

6332	366	AAGAUGCUGUGACUGCGGCUG

6333	367	AUGGUACCUUGAAUCGUGUGG

6334	368	CAACACAGUAUGAUACUGCUC

6335	369	AUCCUUUACCAUCUCCUUCAC

6336	370	UCUUCAUACAUUUCCUCCAAU

6337	371	UUCAAGGAAGUGGACAGCUCC

6338	372	UACCUAUCCGACUUUCGAUGU

6339	373	CUGCCCUUUGAGUACAUCCUU

6340	374	UUGAGAAGAUGCUGUGACUGC

6341	375	UCAAAGAAUGAGAUCCAGAUG

6342	376	UUGGUUUGGUUGCUGAUUUUC

6343	377	AUAGCCGCAAAGUCUGCCUCU

6344	378	UGCAAAUUUCAUCUCGGAGAU

6345	379	UCAGGAGAGUAGCUGACCCAC

6346	380	UGUAGAACAAGGGUCUCCACA

6347	381	CUGAUUGGAGAGACUCACCAA

6348	382	UCUUUCACAUAGGGAUUGCCA

6349	383	UCAAGUAUACUUUCACCUUCU

6350	384	AUUUAGCUUUAACCUCCUGAA

6351	385	AUCCCUUGCGACAUGACGGCA

6352	386	UGCUGGUACACUGACUGAUAG

6353	387	AAUCCAGUUGAGAUCUUUCAC

6354	388	CUGAAGACUAUGUUCCUUGAU

6355	389	AGCAGUUCGUUGUAGAUCUCA

6356	390	UUGGGUGCUUGUAGAACAAGG

6357	391	UACAUUUGGAAUUCAAUAAAA

6358	392	UCCUGAAUCUCUUCUUGGUAA

6359	393	UGAACGAGUGCAGGGAUGGGA

6360	394	UGCAUCCUGGAUAUAAUUCCU

6361	395	AUUUCGAAGGAAUGGUUUCUU

6362	396	UGUUAAUGUUUCCUGCUUCCU

6363	397	ACUCUUCUGAUCUUUGCAGCG

6364	398	UGUUCCUUGAUGAACGAGUGC

6365	399	CUGUAAUUUAGCUUUAACCUC

6366	400	GAACACUCGAGUCAACUUGCU

6367	401	UGGUACCUAUCCGACUUUCGA

6368	402	UCAACCGUUCACCACUCUUCU

6369	403	UCCACAUCAAUGGUGAAGGGC

6370	404	UCGAGUCAACUUGCUGUCACG

6371	405	UUCUCAAUACGGACACAACCC

6372	406	ACAGCUUCUUCAUUUCCUCCU

6373	407	CAACUUGUAGGAGCUCCUCUU

6374	408	UGAAGCUGCUGGGUGGAGGCA

6375	409	UGGGAGAAACUACGACAUCGU

6376	410	UAGGUGGUUAUAAUACAAAAG

6377	411	GACAGCUCGCUGAUCUUGGGG

6378	412	ACCAAGUUUCUGAAGCUCUGU

6379	413	UAAAGCAGUUCGUUGUAGAUC

6380	414	ACUUGUCAGUGACUCCUUGAG

6381	415	UUCACCUUCUCCAUACUGUCC

6382	416	GUAUACUUUCACCUUCUCCAU

6383	417	CAGUGGUAGAGUUUAGCUCUG

6384	418	UCCAAAUGUUCACUGCACCAC

6385	419	AUGGUUUCUUCCCUGGUGGUU

6386	420	AGAGACGACAGAGCAGUCUGA

6387	421	UGUGAAGAAACCUUGGAACAC

6388	422	UUCAACCGUUCACCACUCUUC

6389	423	UGCACAGGGAUUCACAUUGAC

6390	424	UGACAAUCAUGCAGGAACGGC

6391	425	AUACAUGGAGAUGUCAGCUUC

6392	426	AUAAAGCAGUUCGUUGUAGAU

6393	427	CAUGAGAUUACAUAGGUGGUU

6394	428	CUCUUCUAACUUCUUGUCCAC

6395	429	CACACCUAGUCGCCGAAGCUG

6396	430	GACAUCGUCAUCGGACAGCAA

6397	431	ACUAGCACCAUGUUGUUCUGC

6398	432	UAGCUGACCCACCUCAGGGCC

6399	433	ACUCGAGUCAACUUGCUGUCA

6400	434	AAGGGCUUCAGAUCAGGUGUU

6401	435	AACCAGGUUCUGCUUUGACCG

6402	436	UGAACAAUAAUAUCUUUAAUA

6403	437	UUCAUCAUAGGUAGAUGCACA

6404	438	UGAGGGUGGUGGUUCUAACAU

6405	439	UCAGAUCAGGUGUUGGAUGAA

6406	440	UUCCUCCAAUAGUUCCUUUUG

6407	441	AGCUUCUUCAUUUCCUCCUGU

6408	442	ACAUCGUCAUCGGACAGCAAG

6409	443	AGAGAGCUUCUAGCUCUUCAA

6410	444	CAUUGCAAAUUUCAUCUCGGA

6411	445	AAGAGUUUCAUCAUAGGUAGA

6412	446	AAGCUGGACUUUCGCAGCCGC

6413	447	AUCGUCAUCGGACAGCAAGCC

6414	448	UUUCGAAGGAAUGGUUUCUUC

6415	449	UCCUUUACCAUCUCCUUCACA

6416	450	CAGCUUCUUCAUUUCCUCCUG

6417	451	CAACUCUGAAGGUAACAAGGG

6418	452	UGGGUGUCCAAAUGUUCACUG

6419	453	UAGGAUCCGGGCAUAAGGGCU

6420	454	ACAUGAGAUUACAUAGGUGGU

6421	455	ACCACUCUUCUGAUCUUUGCA

6422	456	UACCAUCUCAUUGCAAAUUUC

6423	457	ACAUCCUUUACCAUCUCCUUC

6424	458	UGAAGAAACCUUGGAACACUC

6425	459	UCUUGUCCACAUCAAUGGUGA

6426	460	UAGUGACUCCAUAUGUAUAGA

6427	461	UCAUCACAAGUGGUCAAGGCU

6428	462	CACAACUUGUAGGAGCUCCUC

6429	463	AAGAUGUCAUCACAAGUGGUC

6430	464	AAUCUGCAGCUGUGGACUCAA

6431	465	UCCAUCCUUGAUGGUACCUUG

6432	466	UGGAGAAGCGAAUGUUUGCCG

6433	467	UACAUUUCCUCCAAUAGUUCC

6434	468	UCGAAGCUGGUGCUGGUACCU

6435	469	AUGAACGAGUGCAGGGAUGGG

6436	470	AGCUGUGGACUCAAACAUGGG

6437	471	UCUGCUGAUUGGAGAGACUCA

6438	472	ACCUUUGUGACCGCCGUAGGG

6439	473	CACAUUGACAAUCAUGCAGGA

6440	474	CAGUAUGAUACUGCUCAGCAA

6441	475	UGACCGGUUCUGCUGGUUUUG

6442	476	UGAGAUUACAUAGGUGGUUAU

6443	477	AAAGAAUGAGAUCCAGAUGGA

6444	478	AUGUUCCUUGAUGAACGAGUG

6445	479	UCUCCUUCACAGUUAGGUUGA

6446	480	UCUCUCUGCUGAUUGGAGAGA

6447	481	UCACAAGUGGUCAAGGCUUGA

6448	482	CUGUUGCAUCUGUUCUACCAU

6449	483	UUUCAUCUCGGAGAUGCAUCU

6450	484	UAUUGCAUCCUGGAUAUAAUU

6451	485	CUGCUUUGACCGGUUCUGCUG

6452	486	AGCUCUGGUUCUUACGACCCA

6453	487	AAGUAUACUUUCACCUUCUCC

6454	488	ACACUGACUGAUAGAAGAGAG

6455	489	ACAUAGGUGGUUAUAAUACAA

6456	490	GCAUCUUGCACAUGAAUCCAG

6457	491	UCUGCCCUUUGAGUACAUCCU

6458	492	UUGGAGAGCAAGGGCUUCAGA

6459	493	AGGUGUUAAUGUUUCCUGCUU

6460	494	CUCCUGAAUCUCUUCUUGGUA

6461	495	UGAAGCUCUGUCCGCAACAGC

6462	496	UCCUGAUUGAGAAGAUGCUGU

6463	497	UUCUGAAGCUCUGUCCGCAAC

6464	498	AUGGAACCUGCUGCUUGUCCU

6465	499	AGGAAGUGGACAGCUCCUCCU

6466	500	CUGAUCUUUGCAGCGCUCUGA

6467	501	UAUGAUACUGCUCAGCAAUAC

6468	502	CAUAGGUAGAUGCACAGGGAU

6469	503	ACCUAUCCGACUUUCGAUGUA

6470	504	AAGGUGUAGGAUCCUGAUUGA

6471	505	UGUCCUCAGAUGGAACCUGCU

6472	506	AUAUCAUCAUCAAGGCCUGUG

6473	507	UCUUCAAGGAAGUGGACAGCU

6474	508	UGUUUGAUUAAGAUGUCAUCA

6475	509	UGAUUAAGAUGUCAUCACAAG

6476	510	UCUGGUUGAGGUGGGUGCUGG

6477	511	UUUGACCGGUUCUGCUGGUUU

6478	512	UAAUUCCUGAUAUAUGGUAAA

6479	513	UGACUCCUUGAGGAUAUUUAG

6480	514	AGCUAGUGUCUGAGUAUUGCA

6481	515	UCGCCGAAGCUGGACUUUCGC

6482	516	UCACACCUAGUCGCCGAAGCU

6483	517	CUUUCGAUGUAGACACUCCUC

6484	518	UGUUGCAUCUGUUCUACCAUC

6485	519	UCCCUUGCGACAUGACGGCAG

6486	520	UGUCACGGAAGGGAACCAGGU

6487	521	ACAUGGAGAUGUCAGCUUCAU

6488	522	ACUGCUGUAAUUUAGCUUUAA

6489	523	AAUGGUUUCUUCCCUGGUGGU

6490	524	ACAACAACAUGAGAUUACAUA

6491	525	UCAUGCAGGAACGGCCUCGGC

6492	526	UUGCUCCUCCUGGGAUACUGG

6493	527	UGGUGCUGGUACCUAUCCGAC

6494	528	UGUGAACAAUAAUAUCUUUAA

6495	529	ACCUUCUCCAUACUGUCCUCA

6496	530	ACUUCUUGUCCACAUCAAUGG

6497	531	UGCACAUGAAUCCAGUUGAGA

6498	532	UAGGAGCUUCCAGGCCUCCUC

6499	533	CUUCCUGCAAGAGAGCUUCUA

6500	534	UCUUCCCUGGUGGUUGUUGGU

6501	535	AUAAUUCCUGAUAUAUGGUAA

6502	536	GUACCUUGAAUCGUGUGGGUU

6503	537	AUGUCAUCACAAGUGGUCAAG

6504	538	ACAGCUCGCUGAUCUUGGGGA

6505	539	UACAUAGGUGGUUAUAAUACA

6506	540	UGAUAUAUGGUAAAGCAUAAA

6507	541	AGAGUAGCUGACCCACCUCAG

6508	542	UCAUUGGAGAGCAAGGGCUUC

6509	543	UGGAGAUGUCAGCUUCAUUUU

6510	544	UGACUCCAUAUGUAUAGAUGA

6511	545	CUGAUAGCAGGUUCUUGCGUA

6512	546	AUAAGGGCUGCAGUCUGUUGA

6513	547	AGAUCUUUCACAUAGGGAUUG

6514	548	UGAUUGAGAAGAUGCUGUGAC

6515	549	UGUUUGCCGGGACAGGUAGUG

6516	550	UCAACUUGCUGUCACGGAAGG

6517	551	AGCUCUGCUUUGCACUGCUGU

6518	552	UAGAAAUCAUAUAAGUAAAUA

6519	553	ACAUUCUCAAUACGGACACAA

6520	554	AUGCACAGGGAUUCACAUUGA

6521	555	GUCCAGUUUCACUAGCACCAU

6522	556	CUCAUUGCAAAUUUCAUCUCG

6523	557	GUUGAGAUCUUUCACAUAGGG

6524	558	CAGUCUGAUAGCAGGUUCUUG

6525	559	AGUCAACUUGCUGUCACGGAA

6526	560	UUUCUUCCCUGGUGGUUGUUG

6527	561	ACACCUAGUCGCCGAAGCUGG

6528	562	AUACAUUUCCUCCAAUAGUUC

6529	563	AUCCAGUUGAGAUCUUUCACA

6530	564	GAUGGUACCUUGAAUCGUGUG

6531	565	AACAAGCUCUCUCUGCUGAUU

6532	566	UUAGCUUUAACCUCCUGAAGC

6533	567	ACAAUCAUGCAGGAACGGCCU

6534	568	CAAAUGUUCACUGCACCACUG

6535	569	ACAAGGGUCUCCACAUUCUCA

6536	570	AUCUUCCUGUCGUUCCAACUC

6537	571	AACUUCUUGUCCACAUCAAUG

6538	572	AUGAGAUUACAUAGGUGGUUA

6539	573	AAUCAUGCAGGAACGGCCUCG

6540	574	UUCAGAUCAGGUGUUGGAUGA

6541	575	CUGAUUGAGAAGAUGCUGUGA

6542	576	CAACUUGCUGUCACGGAAGGG

6543	577	AUUACCUCAUUGGAGAGCAAG

6544	578	GUAAUUUAGCUUUAACCUCCU

6545	579	UCAAACAUGGGAGAAACUACG

6546	580	UCCACAACUUGUAGGAGCUCC

6547	581	UGGUCAAGGCUUGACGAAGUU

6548	582	CUGUUCUACCAUCUCAUUGCA

6549	583	UGCUUUGCACUGCUGUAAUUU

6550	584	UGGUACACUGACUGAUAGAAG

6551	585	UGAUCCUCGCAUAGCCGCAAA

6552	586	CUCAGCAAUACAUGCUGCCUU

6553	587	AGAUCACAGAGUGACAGCUCG

6554	588	CCACUCUUCUGAUCUUUGCAG

6555	589	UUCAUACAUUUCCUCCAAUAG

6556	590	AGUGACUCCAUAUGUAUAGAU

6557	591	UCUACCAUCUCAUUGCAAAUU

6558	592	CAACAAGCUCUCUCUGCUGAU

6559	593	CAACAGCCUUAUAUUCUUCUG

6560	594	CAAAGUCUGCCUCUUGCGCUG

6561	595	UGGUCCUGUUUGAUUAAGAUG

6562	596	CACAGAGUGACAGCUCGCUGA

6563	597	UGGUGGUUGUUGGUUUGGUUG

6564	598	UUCCUUCAACCGUUCACCACU

6565	599	AUCCUUGAUGGUACCUUGAAU

6566	600	ACAACCCUGAUCUUCCUGUCG

6567	601	UCAUACAUUUCCUCCAAUAGU

6568	602	CUCAGAUGGAACCUGCUGCUU

6569	603	AGAAACUACGACAUCGUCAUC

6570	604	UCGAAGGAAUGGUUUCUUCCC

6571	605	AAUGUUUGCCGGGACAGGUAG

6572	606	UCAUCUCGGAGAUGCAUCUCC

6573	607	AUAGCAGGUUCUUGCGUACCA

6574	608	GAUGUAGACACUCCUCUUCAA

6575	609	UGGUUCUUACGACCCACUUUU

6576	610	UUCCUGAUAUAUGGUAAAGCA

6577	611	AUGCUGUGACUGCGGCUGGAG

6578	612	AACUUGCUGUCACGGAAGGGA

6579	613	UCCAUACUGUCCUCAGAUGGA

6580	614	AGUCCUUGGGUGCUUGUAGAA

6581	615	UGACGAAGGGCAGCAAUACAG

6582	616	AUGUUCACUGCACCACUGUUC

6583	617	ACUACGACAUCGUCAUCGGAC

6584	618	UGACUGCGGCUGGAGUUCUGG

6585	619	ACGGAAGGGAACCAGGUUCUG

6586	620	ACAUCAAUGGUGAAGGGCUUG

6587	621	GUAGAGUUUAGCUCUGCUUUG

6588	622	UUCAGACCCUGAUUGCUGAUG

6589	623	UCACCACUCUUCUGAUCUUUG

6590	624	UAGAGAGGUGUUAAUGUUUCC

6591	625	AGAGUUUCAUCAUAGGUAGAU

6592	626	CCAGGUUCUGCUUUGACCGGU

6593	627	AAGAGAGCUUCUAGCUCUUCA

6594	628	UCAGGUGUUGGAUGAAGUUGG

6595	629	UUCUACCAUCUCAUUGCAAAU

6596	630	UUCGCAGCCGCAGAGCACAAC

6597	631	CUGGUUGGUACCAAGGCGCUU

6598	632	AUCCCUCCAUCCUUGAUGGUA

6599	633	UGUGCAUAGAAAUCAUAUAAG

6600	634	ACUCCUUGAGGAUAUUUAGUU

6601	635	AGCAAUACAUGCUGCCUUCUU

6602	636	UUCUUCCGAAGGUCCAGUUUC

6603	637	GUUUCUGAAGCUCUGUCCGCA

6604	638	GAUCUGCUUGCUGUCUAGCCA

6605	639	GUCGUUCCAACUCUGAAGGUA

6606	640	AAGGAAUGGUUUCUUCCCUGG

6607	641	GAAGCUGGACUUUCGCAGCCG

6608	642	AAUUCAGACCCUGAUUGCUGA

6609	643	UCCAGGCCUCCUCAGCAUCUU

6610	644	CAGAGCAGUCUGAUAGCAGGU

6611	645	ACAUUUCCUCCAAUAGUUCCU

6612	646	AGCUGGACUUUCGCAGCCGCA

6613	647	AUUUCCUCCUGUCGGAUCUGC

6614	648	ACGGACACAACCCUGAUCUUC

6615	649	AUUGGAGAGCAAGGGCUUCAG

6616	650	UCCUUCAACCGUUCACCACUC

6617	651	UACUUUCACCUUCUCCAUACU

6618	652	UCACCAAGUUUCUGAAGCUCU

6619	653	AGUAGCUGACCCACCUCAGGG

6620	654	UCCUGAAGCUGCUGGGUGGAG

6621	655	UUGCAUCCUGGAUAUAAUUCC

6622	656	AGAGUUUAGCUCUGCUUUGCA

6623	657	CUUCAUUUCCUCCUGUCGGAU

6624	658	ACUGUCGAAGCUGGUGCUGGU

6625	659	AAGUAAAUUUCGAAGGAAUGG

6626	660	UCAGCAAUACAUGCUGCCUUC

6627	661	UUCCCUGGUGGUUGUUGGUUU

6628	662	CUGUCGAAGCUGGUGCUGGUA

6629	663	AGUAAAUUUCGAAGGAAUGGU

6630	664	CUGCAAGAGAGCUUCUAGCUC

6631	665	UCCUGGUUGGUACCAAGGCGC

6632	666	AAGGUCCAGUUUCACUAGCAC

6633	667	UUACAUAGGUGGUUAUAAUAC

6634	668	AUAGGUAGAUGCACAGGGAUU

6635	669	CUUGAUGAACGAGUGCAGGGA

6636	670	CCAUAUGUAUAGAUGAGCCAG

6637	671	CUGCUGCUUGUCCUCUAGGGA

6638	672	UCUCCAUACUGUCCUCAGAUG

6639	673	CUGGUGCUGGUACCUAUCCGA

6640	674	UGCUCAGCAAUACAUGCUGCC

6641	675	ACAUGGGAGAAACUACGACAU

6642	676	CUACUGCUGGUACACUGACUG

6643	677	AGUGGUAGAGUUUAGCUCUGC

6644	678	UCCGAAGGUCCAGUUUCACUA

6645	679	UGUUCCCGCUGUUGCAUCUGU

6646	680	ACAGGGAUUCACAUUGACAAU

6647	681	UGAUGAACGAGUGCAGGGAUG

6648	682	AGGAAUGGUUUCUUCCCUGGU

6649	683	CUCUUCUGAUCUUUGCAGCGC

6650	684	ACACUCCUCUUCAAGGAAGUG

6651	685	UGUGCCCAUCGAUGACUUGUU

6652	686	UCUGUCCGCAACAGCCUUAUA

6653	687	AAUAGGUCAUAAAGCAGUUCG

6654	688	CUCCUCAGCAUCUUGCACAUG

6655	689	CUUAUGCAACUCUUCAGUGGU

6656	690	GUACACUGACUGAUAGAAGAG

6657	691	UGAAGACUAUGUUCCUUGAUG

6658	692	GAGGUAGAGACGACAGAGCAG

6659	693	CUUGUCCACAUCAAUGGUGAA

6660	694	UGAGUAUUGCAUCCUGGAUAU

6661	695	CUUCUGAUCUUUGCAGCGCUC

6662	696	UCUAGGGAGGUAGAGACGACA

6663	697	UCCCGCUCCUGAAUCUCUUCU

6664	698	UAGGUAGAUGCACAGGGAUUC

6665	699	CAUUUCCUCCAAUAGUUCCUU

6666	700	AGCAGGGACAGCUUCUUCAUU

6667	701	UCUGCUUUGCACUGCUGUAAU

6668	702	UGUAGAUCUCAAAGAAUGAGA

6669	703	GCUAGUGUCUGAGUAUUGCAU

6670	704	ACUGCACCACUGUUCCCGCUG

6671	705	AAUAAUAUCUUUAAUAUAACU

6672	706	AUCGGACAGCAAGCCCGCUGG

6673	707	UCCUGCUUCCUUCAACCGUUC

6674	708	UAUGUUCCUUGAUGAACGAGU

6675	709	AGGUUGAAGAAGGAUGCCUGU

6676	710	CAAUAUCAUCAUCAAGGCCUG

6677	711	AGACCUAUUUCUUCAGGAGAG

6678	712	GUUGUUCUGCAGUUCAGCCAG

6679	713	CUGCAGUCUGUUGAGCUUUGG

6680	714	AGUACAUCCUUUACCAUCUCC

6681	715	CAUGAAUCCAGUUGAGAUCUU

6682	716	CAUCGGACAGCAAGCCCGCUG

6683	717	CUCCUGUCGGAUCUGCUUGCU

6684	718	AUCUUUGCAGCGCUCUGAGCC

6685	719	AAGGGUCUCCACAUUCUCAAU

6686	720	AAUACGGACACAACCCUGAUC

6687	721	CAUUUCCUCCUGUCGGAUCUG

6688	722	UCACUGCACCACUGUUCCCGC

6689	723	AGUUAGUGACUCCAUAUGUAU

6690	724	AUCUUUCACAUAGGGAUUGCC

6691	725	AGAUGGAACCUGCUGCUUGUC

6692	726	AUAGAAAUCAUAUAAGUAAAU

6693	727	AGAGACCUAUUUCUUCAGGAG

6694	728	UGAGCGUAGGAUCCGGGCAUA

6695	729	UCGUUCCAACUCUGAAGGUAA

6696	730	CAAGGGUCUCCACAUUCUCAA

6697	731	GAACCUGCUGCUUGUCCUCUA

6698	732	AGGCUAUUGAAGAUCAGCGCC

6699	733	CUAGUCGCCGAAGCUGGACUU

6700	734	AUGGGAGAAACUACGACAUCG

6701	735	CUUCCUUCAACCGUUCACCAC

6702	736	AUGCUGCCUUCUUCCGAAGGU

6703	737	CUUCUAACUUCUUGUCCACAU

6704	738	AGAAGAUGCUGUGACUGCGGC

6705	739	UUCCCGCUGUUGCAUCUGUUC

6706	740	CAACCCUGAUCUUCCUGUCGU

6707	741	AAUUUCGAAGGAAUGGUUUCU

6708	742	AGAGAGGUGUUAAUGUUUCCU

6709	743	GAUGUCAUCACAAGUGGUCAA

6710	744	AAGGGCAGCAAUACAGCGGCC

6711	745	AUCAUGCAGGAACGGCCUCGG

6712	746	GCAUCCUGGAUAUAAUUCCUG

6713	747	CAACUCUUCAGUGGUAGAGUU

6714	748	UCUGUUCUACCAUCUCAUUGC

6715	749	ACGCCGUGAGCGUAGGAUCCG

6716	750	AAUGAGAUCCAGAUGGAGAAG

6717	751	ACAAGCUCUCUCUGCUGAUUG

6718	752	UCUCAAAGAAUGAGAUCCAGA

6719	753	UGGUUGGUACCAAGGCGCUUU

6720	754	AGUAUACUUUCACCUUCUCCA

6721	755	AAAUUUCAUCUCGGAGAUGCA

6722	756	UCUCGGAGAUGCAUCUCCAGC

6723	757	CUGAAGCUCUGUCCGCAACAG

6724	758	GUUAAUGUUUCCUGCUUCCUU

6725	759	UUCGAAGGAAUGGUUUCUUCC

6726	760	CUGAAGGUGUAGGAUCCUGAU

6727	761	AAUACAGCGGCCCAGGGUGUG

6728	762	GUAGGAGCUCCUCUUUGCCAU

6729	763	ACGAAGGGCAGCAAUACAGCG

6730	764	AGAAGCGAAUGUUUGCCGGGA

6731	765	CACUAGCACCAUGUUGUUCUG

6732	766	GAGAAGAUGCUGUGACUGCGG

6733	767	AGACUCACCAAGUUUCUGAAG

6734	768	AGUAUGAUACUGCUCAGCAAU

6735	769	CAGCCUAGGUCCGAAGACGUG

6736	770	CAUCAUAGGUAGAUGCACAGG

6737	771	CUGCUUGUCCUCUAGGGAGGU

6738	772	ACAGAGCAGUCUGAUAGCAGG

6739	773	UCCGACUUUCGAUGUAGACAC

6740	774	AGGGAGGUAGAGACGACAGAG

6741	775	AGAGCAAGGGCUUCAGAUCAG

6742	776	CAAACAUGGGAGAAACUACGA

6743	777	AUACUGCUCAGCAAUACAUGC

6744	778	ACUCUGAAGGUAACAAGGGCC

6745	779	ACACAACCCUGAUCUUCCUGU

6746	780	CAUCCUUGAUGGUACCUUGAA

6747	781	CACUGCACCACUGUUCCCGCU

6748	782	UGGAGAGCAAGGGCUUCAGAU

6749	783	GUAGACACUCCUCUUCAAGGA

6750	784	CUUGGGUGCUUGUAGAACAAG

6751	785	GUCGGAUCUGCUUGCUGUCUA

6752	786	UAGAAGAGAGCCCAGCAAUGC

6753	787	UCCUUCACAGUUAGGUUGAAG

6754	788	UCUUCCGAAGGUCCAGUUUCA

6755	789	CUCGCAUAGCCGCAAAGUCUG

6756	790	CUAAUAGGUCAUAAAGCAGUU

6757	791	ACUGCGGCUGGAGUUCUGGUU

6758	792	CAUCACAAGUGGUCAAGGCUU

6759	793	CCUCUUCUAACUUCUUGUCCA

6760	794	ACUCAAACAUGGGAGAAACUA

6761	795	AUGCAGGAACGGCCUCGGCCU

6762	796	GGCAACAAGCUCUCUCUGCUG

6763	797	GUCAUAAAGCAGUUCGUUGUA

6764	798	GUCCUCAGAUGGAACCUGCUG

6765	799	GAAGGAAUGGUUUCUUCCCUG

6766	800	CUUCUAGCUCUUCAAUCUUUU

6767	801	UCCUGGAUAUAAUUCCUGAUA

6768	802	UCCCGCUGUUGCAUCUGUUCU

6769	803	CAAUACGGACACAACCCUGAU

6770	804	AGUCUGGUCCUGUUUGAUUAA

6771	805	UCACGGAAGGGAACCAGGUUC

6772	806	UGCCGGGACAGGUAGUGGGGC

6773	807	CACUGCUGUAAUUUAGCUUUA

6774	808	UGGAUAUAAUUCCUGAUAUAU

6775	809	AGGAUGCCUGUCCCACUUCUG

6776	810	UGAUAGCAGGUUCUUGCGUAC

6777	811	ACUUUCGCAGCCGCAGAGCAC

6778	812	UUCAUUUCCUCCUGUCGGAUC

6779	813	GAAGGGAACCAGGUUCUGCUU

6780	814	UCCUCAGCAUCUUGCACAUGA

6781	815	GAGUACAUCCUUUACCAUCUC

6782	816	CAUCUCGGAGAUGCAUCUCCA

6783	817	GUGAACAAUAAUAUCUUUAAU

6784	818	CUGUCGGAUCUGCUUGCUGUC

6785	819	UCCUCUAGGGAGGUAGAGACG

6786	820	AGAAGGAUGCCUGUCCCACUU

6787	821	GAGUCAACUUGCUGUCACGGA

6788	822	UGUUGGUUUGGUUGCUGAUUU

6789	823	AGAUGCUGUGACUGCGGCUGG

6790	824	AGUGGACAGCUCCUCCUCUUG

6791	825	UGCUGCCUUCUUCCGAAGGUC

6792	826	CAAGGAAGUGGACAGCUCCUC

6793	827	GACAGAGCAGUCUGAUAGCAG

6794	828	CUGUGGACUCAAACAUGGGAG

6795	829	UGAAUCUCUUCUUGGUAAAAA

6796	830	ACCUCCUGAAGCUGCUGGGUG

6797	831	CUCAAGUAUACUUUCACCUUC

6798	832	GCUAUUGAAGAUCAGCGCCAG

6799	833	ACCGUUCACCACUCUUCUGAU

6800	834	UCCUCCUCUUGGAGGCCUCCA

6801	835	UCCUCAGAUGGAACCUGCUGC

6802	836	AUAGGUGGUUAUAAUACAAAA

6803	837	CACAUCAAUGGUGAAGGGCUU

6804	838	CAAGAGAGCUUCUAGCUCUUC

6805	839	GCUUCUAGCUCUUCAAUCUUU

6806	840	UCCGCAACAGCCUUAUAUUCU

6807	841	UCCCUGGUGGUUGUUGGUUUG

6808	842	CACUCGAGUCAACUUGCUGUC

6809	843	GACUGCUCUUCUCUUUCCCCA

6810	844	GAGAGACUCACCAAGUUUCUG

6811	845	GAGACGACAGAGCAGUCUGAU

6812	846	UUCUUCCCUGGUGGUUGUUGG

6813	847	UCAGUGACUCCUUGAGGAUAU

6814	848	AGGAGAGUAGCUGACCCACCU

6815	849	CUGACUGAUAGAAGAGAGCCC

6816	850	AUCCCGCUCCUGAAUCUCUUC

6817	851	GUAAAUUUCGAAGGAAUGGUU

6818	852	CUUUGCACUGCUGUAAUUUAG

6819	853	AACAAGGGCCUAACCCUCAAG

6820	854	CUCUGCUUUGCACUGCUGUAA

6821	855	CUUGUCAGUGACUCCUUGAGG

6822	856	AUGGAGAUGUCAGCUUCAUUU

6823	857	GAAACUACGACAUCGUCAUCG

6824	858	AGUCUGCCUCUUGCGCUGUUG

6825	859	GAGUUAGUGACUCCAUAUGUA

6826	860	ACAAUAAUAUCUUUAAUAUAA

6827	861	UCCUCUUCAAGGAAGUGGACA

6828	862	GUGUAGAGAGGUGUUAAUGUU

6829	863	CACCAAGUUUCUGAAGCUCUG

6830	864	ACUCACACCUAGUCGCCGAAG

6831	865	GUUCACCACUCUUCUGAUCUU

6832	866	ACCUAUUUCUUCAGGAGAGUA

6833	867	CGAGUCAACUUGCUGUCACGG

6834	868	AGAGACUCACCAAGUUUCUGA

6835	869	ACCUUGAAUCGUGUGGGUUUU

6836	870	CACAGUUAGGUUGAAGAAGGA

6837	871	AGGUCAUAAAGCAGUUCGUUG

6838	872	UCCUCUUGGAGGCCUCCAUUU

6839	873	AACAUGGGAGAAACUACGACA

6840	874	GUCUGAGUAUUGCAUCCUGGA

6841	875	CUUCAACCGUUCACCACUCUU

6842	876	CAGUUUCACUAGCACCAUGUU

6843	877	CACCUUCUCCAUACUGUCCUC

6844	878	AACCUUUGUGACCGCCGUAGG

6845	879	CAUAGCCGCAAAGUCUGCCUC

6846	880	CUUUCACAUAGGGAUUGCCAU

6847	881	AACCCUCAAGUAUACUUUCAC

6848	882	CAUCUGUUCUACCAUCUCAUU

6849	883	GUCUGAUAGCAGGUUCUUGCG

6850	884	AUGGAGAAGCGAAUGUUUGCC

6851	885	GUCUCCACAUUCUCAAUACGG

6852	886	AUUACAUAGGUGGUUAUAAUA

6853	887	UGCGGCUGGAGUUCUGGUUGA

6854	888	CAAGUGGUCAAGGCUUGACGA

6855	889	UGAUCUUCCUGUCGUUCCAAC

6856	890	ACCUAGUCGCCGAAGCUGGAC

6857	891	CUCCUUCACAGUUAGGUUGAA

6858	892	AGGAUCCUGAUUGAGAAGAUG

6859	893	CGUCAUCGGACAGCAAGCCCG

6860	894	AUCUGCAGCUGUGGACUCAAA

6861	895	UCACUAGCACCAUGUUGUUCU

6862	896	UCAUCCCGCUCCUGAAUCUCU

6863	897	UCUGAAGCUCUGUCCGCAACA

6864	898	GCAUCUGUUCUACCAUCUCAU

6865	899	AGAUGCACAGGGAUUCACAUU

6866	900	AGCUCUCUCUGCUGAUUGGAG

6867	901	GUUUAGCUCUGCUUUGCACUG

6868	902	GAGUGACAGCUCGCUGAUCUU

6869	903	AGGUAACAAGGGCCUAACCCU

6870	904	GAAGAAACCUUGGAACACUCG

6871	905	AUAUAUGGUAAAGCAUAAAAG

6872	906	GAGAUCCAGAUGGAGAAGCGA

6873	907	CAUACAUUUCCUCCAAUAGUU

6874	908	ACCACUGUUCCCGCUGUUGCA

6875	909	CUCACCAAGUUUCUGAAGCUC

6876	910	AUCUCAUUGCAAAUUUCAUCU

6877	911	CUGUUCCCGCUGUUGCAUCUG

6878	912	GAGAAACUACGACAUCGUCAU

6879	913	AGCACCAUGUUGUUCUGCAGU

6880	914	AUACGGACACAACCCUGAUCU

6881	915	AAGAGAGCCCAGCAAUGCCAC

6882	916	CUCGAGUCAACUUGCUGUCAC

6883	917	AAGGAUGCCUGUCCCACUUCU

6884	918	UUGCGACAUGACGGCAGGGGC

6885	919	GAGAGGUGUUAAUGUUUCCUG

6886	920	AAUCAUAUAAGUAAAUAAAAA

6887	921	CAAUCAUGCAGGAACGGCCUC

6888	922	GGGAUUCACAUUGACAAUCAU

6889	923	AGGUUCUUGCGUACCACAGAC

6890	924	UCAUUUCCUCCUGUCGGAUCU

6891	925	CAUCCCGCUCCUGAAUCUCUU

6892	926	GUUCUGCUUUGACCGGUUCUG

6893	927	UGCUACAUUUGGAAUUCAAUA

6894	928	CUUGUAGAACAAGGGUCUCCA

6895	929	AGGUAGAGACGACAGAGCAGU

6896	930	UGCUGUCACGGAAGGGAACCA

6897	931	CUUUGACCGGUUCUGCUGGUU

6898	932	GAAGAUGCUGUGACUGCGGCU

6899	933	CAAGUAUACUUUCACCUUCUC

6900	934	GGGUGCUUGUAGAACAAGGGU

6901	935	CACCUAGUCGCCGAAGCUGGA

6902	936	AGCCGCAAAGUCUGCCUCUUG

6903	937	GGUACCUAUCCGACUUUCGAU

6904	938	CGACUUUCGAUGUAGACACUC

6905	939	GAUGCUGUGACUGCGGCUGGA

6906	940	CAGACCCUGAUUGCUGAUGGG

6907	941	AUACUUUCACCUUCUCCAUAC

6908	942	AGGGCUUCAGAUCAGGUGUUG

6909	943	AGAUCCAGAUGGAGAAGCGAA

6910	944	ACUUGCUGUCACGGAAGGGAA

6911	945	AGAGGUGUUAAUGUUUCCUGC

6912	946	GAAACCUUGGAACACUCGAGU

6913	947	CAAAGCUCUGGUUCUUACGAC

6914	948	CUCAUUGGAGAGCAAGGGCUU

6915	949	CAUCUUGCACAUGAAUCCAGU

6916	950	UGAGUACAUCCUUUACCAUCU

6917	951	UGUGGACUCAAACAUGGGAGA

6918	952	CUGCUGAUUGGAGAGACUCAC

6919	953	ACGACAUCGUCAUCGGACAGC

6920	954	CAGUUCGUUGUAGAUCUCAAA

6921	955	CUCCUUGAGGAUAUUUAGUUU

6922	956	GAGAAGCGAAUGUUUGCCGGG

6923	957	AGAAAGGAUCCCUUGCGACAU

6924	958	CGACAGAGCAGUCUGAUAGCA

6925	959	UGUAGACACUCCUCUUCAAGG

6926	960	CGAAGGAAUGGUUUCUUCCCU

6927	961	UGGAGGCCUCCAUUUAGCAGG

6928	962	AUGUUUGCCGGGACAGGUAGU

6929	963	GAUCACAGAGUGACAGCUCGC

6930	964	CCGCUCCUGAAUCUCUUCUUG

6931	965	AGCAAUACAGCGGCCCAGGGU

6932	966	AAAGGAUCCCUUGCGACAUGA

6933	967	UCACAGUUAGGUUGAAGAAGG

6934	968	AGUUGAGAUCUUUCACAUAGG

6935	969	AUUGACAAUCAUGCAGGAACG

6936	970	CUGAUACUUAUGCAACUCUUC

6937	971	ACUCUUCAGUGGUAGAGUUUA

6938	972	CCUGAUUGAGAAGAUGCUGUG

6939	973	UGAAUCCAGUUGAGAUCUUUC

6940	974	GCAAGAGAGCUUCUAGCUCUU

6941	975	CCUCAAGUAUACUUUCACCUU

6942	976	AAGCUCUGGUUCUUACGACCC

6943	977	GACUGAUAGAAGAGAGCCCAG

6944	978	AAAUCAUAUAAGUAAAUAAAA

6945	979	CUGGUUCUUACGACCCACUUU

6946	980	CGAAGGGCAGCAAUACAGCGG

6947	981	CUUCACAGUUAGGUUGAAGAA

6948	982	AGCAGUCUGAUAGCAGGUUCU

6949	983	GUAGAGACGACAGAGCAGUCU

6950	984	GGAGUUUCAACACAGUAUGAU

6951	985	UGCCCAUCGAUGACUUGUUUC

6952	986	UCCACAUUCUCAAUACGGACA

6953	987	ACCUGAAGACUAUGUUCCUUG

6954	988	UGUCAUCACAAGUGGUCAAGG

6955	989	CCUUGGAGUUUCAACACAGUA

6956	990	CUGAGUAUUGCAUCCUGGAUA

6957	991	CUUUGAGUACAUCCUUUACCA

6958	992	GUGAGCGUAGGAUCCGGGCAU

6959	993	GUACAUCCUUUACCAUCUCCU

6960	994	CUUCUUCCGAAGGUCCAGUUU

6961	995	GGUACCUUGAAUCGUGUGGGU

6962	996	AUCCGGGCAUAAGGGCUGCAG

6963	997	CUUGGAGUUUCAACACAGUAU

6964	998	AAGGUAACAAGGGCCUAACCC

6965	999	GUGCUGGUACCUAUCCGACUU

6966	1000	UUACCUCAUUGGAGAGCAAGG

6967	1001	UGAGAUCCAGAUGGAGAAGCG

6968	1002	CUGGAGUUCUGGUUGAGGUGG

6969	1003	CAGCUGUGGACUCAAACAUGG

6970	1004	CUGAGUUAGUGACUCCAUAUG

6971	1005	ACCAUCUCCUUCACAGUUAGG

6972	1006	GACUCCAUAUGUAUAGAUGAG

6973	1007	GUUGUUGGUUUGGUUGCUGAU

6974	1008	GCAACAAGCUCUCUCUGCUGA

TABLE 10

Results for LTB. Score threshold: 70.
Design: siRNA 21 nt.

SEQ
ID	siRNA_	siRNA guide strand/
NO	id	AS Sequence

6975	1	UUAUCGGCAGCACUGAAGCUU

6976	2	UGUUCCUUCGUCGUCUCCCAG

6977	3	UCAAUUUCCAAACAGUCUCCU

6978	4	UUUCCAAACAGUCUCCUACAU

6979	5	UUGACGUACACCCUCUCGCCC

6980	6	UUUAUCGGCAGCACUGAAGCU

6981	7	UUCUGAAACCCAGUCCUCCCU

6982	8	UAAUAGAGGCCGUCCUGCGGG

6983	9	UCGUGUACCAGAGAGGCCCGU

6984	10	UACAGAGAGCUGCGCAGCGUG

6985	11	UCCUUCGUCGUCUCCCAGCCU

6986	12	UCGAGCAGCAGCUCGGGAGUG

6987	13	UCUGAAACCCAGUCCUCCCUG

6988	14	UUCACGCACUCGCACCACGCA

6989	15	UUCCAAACAGUCUCCUACAUU

6990	16	AAGAAGGUCUUCCCUCUCGCG

6991	17	AUAUUCACGCACUCGCACCAC

6992	18	UCCAGCACUGGAGUCACCGUC

6993	19	ACUGAUGUUGACGUACACCCU

6994	20	UCGCGAAGUCCACCAUAUCGG

6995	21	UAGCCGACGAGACAGUAGAGG

6996	22	UCACGCACUCGCACCACGCAC

6997	23	AAGCUUUCCAUUCUUUAUUUU

6998	24	UAUCGGCAGCACUGAAGCUUU

6999	25	AUGUUGACGUACACCCUCUCG

7000	26	AGAAGGUCUUCCCUCUCGCGA

7001	27	AACAAGGUCACCAGAGAAGUG

7002	28	AACGCCUGUUCCUUCGUCGUC

7003	29	UCGUCUCCCAGCCUAGCCCCU

7004	30	UCGGCGUCCGAGAACUGCGUC

7005	31	AAUAUUCACGCACUCGCACCA

7006	32	UCGUCAGAAACGCCUGUUCCU

7007	33	UACCAGAGAGGCCCGUACCCU

7008	34	ACUGGAGUCACCGUCUCGGCG

7009	35	UAUGAGGUGGGCAGCUGGGAG

7010	36	UGAUGUUGACGUACACCCUCU

7011	37	AUCAAUUUCCAAACAGUCUCC

7012	38	UGACGUACACCCUCUCGCCCC

7013	39	AGUAGAGGUAAUAGAGGCCGU

7014	40	UGAAGCUUUCCAUUCUUUAUU

7015	41	CUGAUGUUGACGUACACCCUC

7016	42	UCCCGCUCGUCAGAAACGCCU

7017	43	AGCACUGGAGUCACCGUCUCG

7018	44	CAAUUUCCAAACAGUCUCCUA

7019	45	AAACGCCUGUUCCUUCGUCGU

7020	46	UAUUCACGCACUCGCACCACG

7021	47	AUAGAGGCCGUCCUGCGGGAG

7022	48	GACAGUGAUAGGCACCGCCAG

7023	49	AGCUUCUGAAACCCAGUCCUC

7024	50	AGCAACAAGGUCACCAGAGAA

7025	51	UUCCUUCGUCGUCUCCCAGCC

7026	52	UCCGAGAACUGCGUCCCGCUC

7027	53	AGAGCUGCGCAGCGUGACCGA

7028	54	CUGCGCAGCGUGACCGAGCGG

7029	55	AAUAGAGGCCGUCCUGCGGGA

7030	56	UGAAACCCAGUCCUCCCUGAU

7031	57	UGUUGACGUACACCCUCUCGC

7032	58	ACCCAGUCCUCCCUGAUCCUG

7033	59	ACAAGGUCACCAGAGAAGUGG

7034	60	UGGAGUCACCGUCUCGGCGCC

7035	61	AUCGGCAGCACUGAAGCUUUC

7036	62	AAUUUCCAAACAGUCUCCUAC

7037	63	AGAAACGCCUGUUCCUUCGUC

7038	64	UUCAGCGGAGCGCCUAUGAGG

7039	65	UCACCGUCUCGGCGCCCUCGA

7040	66	AACUGCGUCCCGCUCGUCAGA

7041	67	AUUCACGCACUCGCACCACGC

7042	68	AAAGAAGGUCUUCCCUCUCGC

7043	69	GUACAGAGAGCUGCGCAGCGU

7044	70	AGACAGUAGAGGUAAUAGAGG

7045	71	CAGUAGAGGUAAUAGAGGCCG

7046	72	UCCAAACAGUCUCCUACAUUU

7047	73	CAAACAGUCUCCUACAUUUUU

7048	74	GUAAUAGAGGCCGUCCUGCGG

7049	75	UUCGUCGUCUCCCAGCCUAGC

7050	76	AAGGUCUUCCCUCUCGCGAAG

7051	77	CUGUUCCUUCGUCGUCUCCCA

7052	78	CCUUCGUCGUCUCCCAGCCUA

7053	79	UGACUGAUGUUGACGUACACC

7054	80	UGCACCAGGCCGCCGAACCCC

7055	81	GAGGUAAUAGAGGCCGUCCUG

7056	82	UCUUCCCUCUCGCGAAGUCCA

7057	83	AGAGGUAAUAGAGGCCGUCCU

7058	84	AUUUCCAAACAGUCUCCUACA

7059	85	ACAGUAGAGGUAAUAGAGGCC

7060	86	CAGCUUCUGAAACCCAGUCCU

7061	87	AACCCAGUCCUCCCUGAUCCU

7062	88	UCCGGAGCUGCACCAGGCCGC

7063	89	UCAGAAACGCCUGUUCCUUCG

7064	90	UCGUCGUCUCCCAGCCUAGCC

7065	91	CAGCACUGGAGUCACCGUCUC

7066	92	CAGUCCUCCCUGAUCCUGGGG

7067	93	ACUGAAGCUUUCCAUUCUUUA

7068	94	UGCGCAGCGUGACCGAGCGGC

7069	95	UCAGCGGAGCGCCUAUGAGGU

7070	96	UCCCUCUCGCGAAGUCCACCA

7071	97	AGCACUGAAGCUUUCCAUUCU

7072	98	UAGAGGUAAUAGAGGCCGUCC

7073	99	ACUCGCACCACGCACUCAUAU

7074	100	CUCGGCGUCCGAGAACUGCGU

7075	101	AGGACAGUGAUAGGCACCGCC

7076	102	GCGAAGUCCACCAUAUCGGGG

7077	103	GAGCUGCGCAGCGUGACCGAG

7078	104	GAGAACUGCGUCCCGCUCGUC

7079	105	ACGCACUCGCACCACGCACUC

7080	106	GCACUGAAGCUUUCCAUUCUU

7081	107	ACAGCUAGCAGGAGGGAACCC

7082	108	ACGCCUGUUCCUUCGUCGUCU

7083	109	CACCACGCACUCAUAUUCCCU

7084	110	GUAGAGGUAAUAGAGGCCGUC

7085	111	ACAGAGAGCUGCGCAGCGUGA

7086	112	GAGACAGUAGAGGUAAUAGAG

7087	113	ACUGCGUCCCGCUCGUCAGAA

7088	114	CGCGAAGUCCACCAUAUCGGG

7089	115	GUAGCCGACGAGACAGUAGAG

7090	116	CACUGAAGCUUUCCAUUCUUU

7091	117	UCGGCAGCACUGAAGCUUUCC

TABLE 11

GalNAC-siRNA conjugates.

SEQ		Passenger	SEQ	guide
ID		strand	ID	strand
NO	siRNA_id	(sense)	NO	(antisense)

7092	Mfap4.1356	GCUACUGCUC	7141	UUCAGAGUUG
		AACUCUGAA		AGCAGUAGCC
				G

7093	Mfap4.760	GCUUCUAUUA	7142	UUGAGGGAGU
		CUCCCUCAA		AAUAGAAGCC
				U

7094	Grhpr.361	GACAGAUGCC	7143	UUCUGCAGUG
		ACUGCAGAA		GCAUCUGUCA
				G

7095	lftg1.698	CGACAUUGAC	7144	UUAGAGGCAG
		UGCCUCUAA		UCAAUGUCGU
				G

7096	ltfg1.680	CACUGAUUAU	7145	UUGAAGUCCA
		GGACUUCAA		UAAUCAGUGG
				U

7146	Mfap4.1356	5′-cscsaGf	7151	5′-UfsUfsc
	modified	cUfaCfuGfc		AfgAfgUfuG
		UfcAfaCfuC		faGfcAfgUf
		fuGfaAfs		aGfcsdTsdT
		(NHC6)(Gal		-3′
		NAc3)-3′

7147	Mfap4.760	5′-cscsaGf	7152	5′-UfsUfsg
	modified	cUfuCfuAfu		AfgGfgAfgU
		UfaCfuCfcC		faAfuAfgAf
		fuCfaAfs		aGfcsdTsdT
		(NHC6)(Gal		-3′
		NAc3)-3′

7148	Grhpr.361	5′-cscsaGf	7153	5′-UfsUfsc
	modified	aCfaGfaUfg		UfgCfaGfuG
		CfcAfcUfgC		fgCfaUfcUf
		faGfaAfs		gUfcsdTsdT
		(NHC6)(Gal		-3′
		NAc3)-3′

7149	Iftg1.698	5′-cscsaCf	7154	5′-UfsUfsa
	modified	gAfcAfuUfg		GfaGfgCfaG
		AfcUfgCfcU		fuCfaAfuGf
		fcUfaAfs		uCfgsdTsdT
		(NHC6)(Gal		-3′
		NAc3)-3′

7150	Itfg1.680	5′-cscsaCf	7155	5′-UfsUfsg
	modified	aCfuGfaUfu		AfaGfuCfcA
		AfuGfgAfcU		fuAfaUfcAf
		fuCfaAfs		gUfgsdTsdT
		(NHC6)(Gal		-3′
		NAc3)-3′

n: 2′-O-methyl residues
Nf: 2′-Fluoro residues
s: phosphorothioate backbone modification
dN: DNA residue
(NHC6): Aminohexyl linker
(GalNAc3): Trinatennary GalNAc cluster

TABLE 12

Human shRNAs sequences
(sense-loop-antisense sequences)

SEQ
ID	shRNA-
NO:	id	Nucleic acid sequence

7097	huMfap4.1602	TGCTGTTGACAGTGAGCGATAGGGA
		CTGAAGGTCTCAATATAGTGAAGCC
		ACAGATGTATATTGAGACCTTCAGT
		CCCTACTGCCTACTGCCTCGGA

7098	huMfap4.1603	TGCTGTTGACAGTGAGCGCAGGGAC
		TGAAGGTCTCAATAATAGTGAAGCC
		ACAGATGTATTATTGAGACCTTCAG
		TCCCTATGCCTACTGCCTCGGA

7099	huMfap4.1642	TGCTGTTGACAGTGAGCGAAACTGG
		CTTCATACACACAAATAGTGAAGCC
		ACAGATGTATTTGTGTGTATGAAGC
		CAGTTCTGCCTACTGCCTCGGA

7100	huMfap4.1812	TGCTGTTGACAGTGAGCGCCAGTGT
		AATAATAACATAATATAGTGAAGCC
		ACAGATGTATATTATGTTATTATTA
		CACTGTTGCCTACTGCCTCGGA

7101	huMfap4.318	TGCTGTTGACAGTGAGCGACAGAAG
		AGATTCAATGGCTCATAGTGAAGCC
		ACAGATGTATGAGCCATTGAATCTC
		TTCTGGTGCCTACTGCCTCGGA

7102	huMfap4.350	TGCTGTTGACAGTGAGCGCCCGCGG
		CTGGAATGACTACAATAGTGAAGC
		CACAGATGTATTGTAGTCATTCCAG
		CCGCGGATGCCTACTGCCTCGGA

7103	huGrhpr.1125	TGCTGTTGACAGTGAGCGAAAGGTG
		TGATTCTCTGAGGAATAGTGAAGCC
		ACAGATGTATTCCTCAGAGAATCAC
		ACCTTCTGCCTACTGCCTCGGA

7104	huGrhpr.1172	TGCTGTTGACAGTGAGCGCCACATT
		GGTGTTGGACACATTTAGTGAAGCC
		ACAGATGTAAATGTGTCCAACACCA
		ATGTGATGCCTACTGCCTCGGA

7105	huGrhpr.626	TGCTGTTGACAGTGAGCGCTCCAGG
		CAGAGTTTGTGTCTATAGTGAAGCC
		ACAGATGTATAGACACAAACTCTGC
		CTGGAATGCCTACTGCCTCGGA

7106	huGrhpr.750	TGCTGTTGACAGTGAGCGCAACAGC
		TGTGTTCATCAACATTAGTGAAGCC
		ACAGATGTAATGTTGATGAACACAG
		CTGTTTTGCCTACTGCCTCGGA

7107	huGrhpr.752	TGCTGTTGACAGTGAGCGCCAGCTG
		TGTTCATCAACATCATAGTGAAGCC
		ACAGATGTATGATGTTGATGAACAC
		AGCTGTTGCCTACTGCCTCGGA

7108	huGrhpr.954	TGCTGTTGACAGTGAGCGACATGTC
		CTTGTTGGCAGCTAATAGTGAAGCC
		ACAGATGTATTAGCTGCCAACAAGG
		ACATGGTGCCTACTGCCTCGGA

7109	hultfg1.1364	TGCTGTTGACAGTGAGCGAAAGCAG
		ATGCTTATTTTGTTATAGTGAAGCC
		ACAGATGTATAACAAAATAAGCATC
		TGCTTCTGCCTACTGCCTCGGA

7110	hultfg1.1683	TGCTGTTGACAGTGAGCGACCAGCT
		AATTGTCATTCCATATAGTGAAGCC
		ACAGATGTATATGGAATGACAATTA
		GCTGGGTGCCTACTGCCTCGGA

7111	hultfg1.2162	TGCTGTTGACAGTGAGCGATCCAGT
		GTTTGTGTATTTATATAGTGAAGCC
		A
		CAGATGTATATAAATACACAAACAC
		TGGAGTGCCTACTGCCTCGGA

7112	hultfg1.2163	TGCTGTTGACAGTGAGCGCCCAGTG
		TTTGTGTATTTATAATAGTGAAGCC
		ACAGATGTATTATAAATACACAAAC
		ACTGGATGCCTACTGCCTCGGA

7113	hultfg 1.641	TGCTGTTGACAGTGAGCGACAGCAT
		TGACCACTACAAGTATAGTGAAGCC
		ACAGATGTATACTTGTAGTGGTCAA
		TGCTGGTGCCTACTGCCTCGGA

7114	hultfg1.971	TGCTGTTGACAGTGAGCGATCCTAC
		AAGATTTCAGCAATATAGTGAAGCC
		ACAGATGTATATTGCTGAAATCTTG
		TAGGACTGCCTACTGCCTCGGA

TABLE 13

Mouse shRNA sequences (sense-loop-
antisense sequences)

SEQ
ID
NO	shRNA_id	Nucleic acid sequence

7115	Mfap4.1073	TGCTGTTGACAGTGAGCGAAAAGCC
		AGAAGCTACCTTCTATAGTGAAGCC
		ACAGATGTATAGAAGGTAGCTTCTG
		GCTTTCTGCCTACTGCCTCGGA

7116	Mfap4.1118	TGCTGTTGACAGTGAGCGCCAGCAG
		TTTCCTTACTGCAGATAGTGAAGCC
		ACAGATGTATCTGCAGTAAGGAAAC
		TGCTGATGCCTACTGCCTCGGA

7117	Mfap4.1321	TGCTGTTGACAGTGAGCGCTCCCTC
		AAAATTCACCACCAATAGTGAAGCC
		ACAGATGTATTGGTGGTGAATTTTG
		AGGGATTGCCTACTGCCTCGGA

7118	Mfap4.1356	TGCTGTTGACAGTGAGCGCCGGCTA
		CTGCTCAACTCTGAATAGTGAAGCC
		ACAGATGTATTCAGAGTTGAGCAGT
		AGCCGTTGCCTACTGCCTCGGA

7119	Mfap4.274	TGCTGTTGACAGTGAGCGACAAGTG
		GACGGTTTTCCAGAATAGTGAAGCC
		ACAGATGTATTCTGGAAAACCGTCC
		ACTTGCTGCCTACTGCCTCGGA

7120	Mfap4.760	TGCTGTTGACAGTGAGCGCAGGCTT
		CTATTACTCCCTCAATAGTGAAGCC
		ACAGATGTATTGAGGGAGTAATAGA
		AGCCTTTGCCTACTGCCTCGGA

7121	Grhpr.1009	TGCTGTTGACAGTGAGCGACCCAGC
		GAACTCAAGCTGTAATAGTGAAGCC
		ACAGATGTATTACAGCTTGAGTTCG
		CTGGGCTGCCTACTGCCTCGGA

7122	Grhpr.1187	TGCTGTTGACAGTGAGCGCTGCCAA
		AAGCCTGTAATTCTATAGTGAAGCC
		ACAGATGTATAGAATTACAGGCTTT
		TGGCAATGCCTACTGCCTCGGA

7123	Grhpr.1193	TGCTGTTGACAGTGAGCGCAAGCCT
		GTAATTCTAGCATTATAGTGAAGCC
		ACAGATGTATAATGCTAGAATTACA
		GGCTTTTGCCTACTGCCTCGGA

7124	Grhpr.720	TGCTGTTGACAGTGAGCGACAGCAA
		GGATTTCTTCCAGAATAGTGAAGCC
		ACAGATGTATTCTGGAAGAAATCCT
		TGCTGCTGCCTACTGCCTCGGA

7125	Grhpr.361	TGCTGTTGACAGTGAGCGACTGACA
		GATGCCACTGCAGAATAGTGAAGC
		CACAGATGTATTCTGCAGTGGCATC
		TGTCAGGTGCCTACTGCCTCGGA

7126	Grhpr.787	TGCTGTTGACAGTGAGCGCCAGCAG
		AGGAGATGTGGTAAATAGTGAAGC
		CACAGATGTATTTACCACATCTCCT
		CTGCTGATGCCTACTGCCTCGGA

7127	Grhpr.736	TGCTGTTGACAGTGAGCGACAGCAA
		GGATTTCTTCCAGAATAGTGAAGCC
		ACAGATGTATTCTGGAAGAAATCCT
		TGCTGCTGCCTACTGCCTCGGA

7128	Grhpr.1024	TGCTGTTGACAGTGAGCGCGCCCAG
		CGAACTCAAGCTGTATAGTGAAGC
		CACAGATGTATACAGCTTGAGTTCG
		CTGGGCATGCCTACTGCCTCGGA

7129	Grhpr.1025	TGCTGTTGACAGTGAGCGACCCAGC
		GAACTCAAGCTGTAATAGTGAAGCC
		ACAGATGTATTACAGCTTGAGTTCG
		CTGGGCTGCCTACTGCCTCGGA

7130	lftg1.698	TGCTGTTGACAGTGAGCGCCACGAC
		ATTGACTGCCTCTAATAGTGAAGCC
		ACAGATGTATTAGAGGCAGTCAATG
		TCGTGATGCCTACTGCCTCGGA

7131	Itfg1.376	TGCTGTTGACAGTGAGCGCGCCATC
		CATACACTCAAAAAATAGTGAAGCC
		ACAGATGTATTTTTTGAGTGTATGG
		ATGGCATGCCTACTGCCTCGGA

7132	Itfg1.448	TGCTGTTGACAGTGAGCGCGACGCC
		ATAGTTGCCACCTTATAGTGAAGCC
		ACAGATGTATAAGGTGGCAACTATG
		GCGTCTTGCCTACTGCCTCGGA

7133	Itfg1.694	TGCTGTTGACAGTGAGCGCGAGGCA
		GATGCTTACTTTGTATAGTGAAGCC
		ACAGATGTATACAAAGTAAGCATCT
		GCCTCATGCCTACTGCCTCGGA

7134	Itfg1.2450	TGCTGTTGACAGTGAGCGACCAGAT
		AAAGTTATTCAAGTATAGTGAAGCC
		ACAGATGTATACTTGAATAACTTTA
		TCTGGCTGCCTACTGCCTCGGA

7135	Itfg1.2451	TGCTGTTGACAGTGAGCGACAGATA
		AAGTTATTCAAGTAATAGTGAAGCC
		ACAGATGTATTACTTGAATAACTTT
		ATCTGGTGCCTACTGCCTCGGA

7136	Itfg1.2802	TGCTGTTGACAGTGAGCGCTGGATT
		GTCACCGAAGACATATAGTGAAGCC
		ACAGATGTATATGTCTTCGGTGACA
		ATCCATTGCCTACTGCCTCGGA

7137	Itfg1.2921	TGCTGTTGACAGTGAGCGCAAGCTG
		GTATTTGAATACTAATAGTGAAGCC
		ACAGATGTATTAGTATTCAAATACC
		AGCTTTTGCCTACTGCCTCGGA

7138	Itfg1.680	TGCTGTTGACAGTGAGCGCACCACT
		GATTATGGACTTCAATAGTGAAGCC
		ACAGATGTATTGAAGTCCATAATCA
		GTGGTTTGCCTACTGCCTCGGA

7139	Itfg1.875	TGCTGTTGACAGTGAGCGCCACGAC
		ATTGACTGCCTCTAATAGTGAAGCC
		ACAGATGTATTAGAGGCAGTCAATG
		TCGTGATGCCTACTGCCTCGGA

7140	Itfg1.503	TGCTGTTGACAGTGAGCGCACCACT
		GATTATGGACTTCAATAGTGAAGCC
		ACAGATGTATTGAAGTCCATAATCA
		GTGGTTTGCCTACTGCCTCGGA

TABLE 14

Target sequences.

SEQ ID
NO:	Description	Sequence

7156	Human MFAP4	MKALLALPLLLLLSTPPCAPQVSGIRGDALERFCLQQPLDCDDIYAQGYQSDGVYLIYPSGPSVPVPV
	isoform 1	FCDMTTEGGKWTVFQKRFNGSVSFFRGWNDYKLGFGRADGEYWLGLQNMHLLTLKQKYELRVDLEDFE
	(UniProtKB:	NNTAYAKYADFSISPNAVSAEEDGYTLFVAGFEDGGAGDSLSYHSGQKFSTFDRDQDLFVQNCAALSS
	P55083-1, v2)	GAFWFRSCHFANLNGFYLGGSHLSYANGINWAQWKGFYYSLKRTEMKIRRA

7157	Human MFAP4	MGELSPLQRPLATEGTMKAQGVLLKLALLALPLLLLLSTPPCAPQVSGIRGDALERFCLQQPLDCDDI
	isoform 2	YAQGYQSDGVYLIYPSGPSVPVPVFCDMTTEGGKWTVFQKRFNGSVSFFRGWNDYKLGFGRADGEYWL
	(UniProtKB:	GLQNMHLLTLKQKYELRVDLEDFENNTAYAKYADFSISPNAVSAEEDGYTLFVAGFEDGGAGDSLSYH
	P55083-2)	SGQKFSTFDRDQDLFVQNCAALSSGAFWFRSCHFANLNGFYLGGSHLSYANGINWAQWKGFYYSLKRT
		EMKIRRA

7158	Human GRHPR	MRPVRLMKVFVTRRIPAEGRVALARAADCEVEQWDSDEPIPAKELERGVAGAHGLLCLLSDHVDKRIL
	isoform 1	DAAGANLKVISTMSVGIDHLALDEIKKRGIRVGYTPDVLTDTTAELAVSLLLTTCRRLPEAIEEVKNG
	(UniProtKB:	GWTSWKPLWLCGYGLTQSTVGIIGLGRIGQAIARRLKPFGVQRFLYTGRQPRPEEAAEFQAEFVSTPE
	Q9UBQ7-1, v1)	LAAQSDFIVVACSLTPATEGLCNKDFFQKMKETAVFINISRGDVVNQDDLYQALASGKIAAAGLDVTS
		PEPLPTNHPLLTLKNCVILPHIGSATHRTRNTMSLLAANNLLAGLRGEPMPSELKL

7159	Human GRHPR	MLGGVPTLCGTGNETWTLLALGQAIARRLKPFGVQRFLYTGRQPRPEEAAEFQAEFVSTPELAAQSDF
	isoform 2	IVVACSLTPATEGLCNKDFFQKMKETAVFINISRYPRATLPSKPGEEPSPLLPSGDFLPRGLLVRPQA
	(UniProtKB:	ELAGFHKPNNQLRNSWEYTRPPYREEEPSEWAWPVCFSAVAPTRRGLAHSSVASGSVPREPLQAHYPP
	Q9UBQ7-2)	PQRAGLEDLKGPLEAASHTAEPGFVWLWFSDTLNLMLLGGQTLKLTWS

7160	Human ITFG1	MAAAGRLPSSWALFSPLLAGLALLGVGPVPARALHNVTAELFGAEAWGTLAAFGDLNSDKQTDLFVLR
	(UniProtKB	ERNDLIVFLADQNAPYFKPKVKVSFKNHSALITSVVPGDYDGDSQMDVLLTYLPKNYAKSELGAVIFW
	Q8TB96-1, v1)	GQNQTLDPNNMTILNRTFQDEPLIMDFNGDLIPDIFGITNESNQPQILLGGNLSWHPALTTTSKMRIP
		HSHAFIDLTEDFTADLFLTTLNATTSTFQFEIWENLDGNFSVSTILEKPQNMMVVGQSAFADFDGDGH
		MDHLLPGCEDKNCQKSTIYLVRSGMKQWVPVLQDFSNKGTLWGFVPFVDEQQPTEIPIPITLHIGDYN
		MDGYPDALVILKNTSGSNQQAFLLENVPCNNASCEEARRMFKVYWELTDLNQIKDAMVATFFDIYEDG
		ILDIWLSKGYTKNDFAIHTLKNNFEADAYFVKVIVLSGLCSNDCPRKITPFGVNQPGPYIMYTTVDA
		NGYLKNGSAGQLSQSAHLALQLPYNVLGLGRSANFLDHLYVGIPRPSGEKSIRKQEWTAIIPNSQLIV
		IPYPHNVPRSWSAKLYLTPSNIVLLTAIALIGVCVFILAIIGILHWQEKKADDREKRQEAHRFHFDAM

7161	Human ABCC4	MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEELQGFWDKEV
	isoform 1	LRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEESAKVIQPIFLGKIINYFENYDPMDSVALNTAYA
	(UniProtKB:	YATVLTFCTLILAILHHLYFYHVQCAGMRLRVAMCHMIYRKALRLSNMAMGKTTTGQIVNLLSNDVNK
	015439-1, v3)	FDQVTVFLHFLWAGPLQAIAVTALLWMEIGISCLAGMAVLIILLPLQSCFGKLFSSLRSKTATFTDAR
		IRTMNEVITGIRIIKMYAWEKSFSNLITNLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYV
		LLGSVITASRVFVAVTLYGAVRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKK
		MVHVQDFTAFWDKASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIA
		YVSQQPWVFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQKARVN
		LARAVYQDADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAASQILILKDGKMV
		QKGTYTEFLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVWSQQSSRPSLKDGALESQDTE
		NVPVTLSEENRSEGKVGFQAYKNYFRAGAHWIVFIFLILLNTAAQVAYVLQDWWLSYWANKQSMLNVT
		VNGGGNVTEKLDLNWYLGIYSGLTVATVLFGIARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRN
		PIGRILNRFSKDIGHLDDLLPLTFLDFIQTLLQVVGVVSVAVAVIPWIAIPLVPLGIIFIFLRRYFLE
		TSRDVKRLESTTRSPVFSHLSSSLQGLWTIRAYKAEERCQELFDAHQDLHSEAWFLFLTTSRWFAVRL
		DAICAMFVIIVAFGSLILAKTLDAGQVGLALSYALTLMGMFQWCVRQSAEVENMMISVERVIEYTDLE
		KEAPWEYQKRPPPAWPHEGVIIFDNVNFMYSPGGPLVLKHLTALIKSQEKVGIVGRTGAGKSSLISAL
		FRLSEPEGKIWIDKILTTEIGLHDLRKKMSIIPQEPVLFTGTMRKNLDPFNEHTDEELWNALQEVQLK
		ETIEDLPGKMDTELAESGSNFSVGQRQLVCLARAILRKNQILIIDEATANVDPRTDELIQKKIREKFA
		HCTVLTIAHRLNTIIDSDKIMVLDSGRLKEYDEPYVLLQNKESLFYKMVQQLGKAEAAALTETAKQVY
		FKRNYPHIGHTDHMVTNTSNGQPSTLTIFETAL

7162	Human ABCC4	MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEELQGFWDKEV
	isoform 2	LRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEESAKVIQPIFLGKIINYFENYDPMDSVALNTAYA
	(UniProtKB:	YATVLTFCTLILAILHHLYFYHVQCAGMRLRVAMCHMIYRKALRLSNMAMGKTTTGQIVNLLSNDVNK
	O15439-2)	FDQVTVFLHFLWAGPLQAIAVTALLWMEIGISCLAGMAVLIILLPLQSCFGKLFSSLRSKTATFTDAR
		IRTMNEVITGIRIIKMYAWEKSFSNLITNLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYV
		LLGSVITASRVFVAVTLYGAVRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKK
		MVHVQDFTAFWDKASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIA
		YVSQQPWVFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQKARVN
		LARAVYQDADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAASQILILKDGKMV
		QKGTYTEFLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVW
		SQQSSRPSLKDGALESQDVAYVLQDWWLSYWANKQSMLNVTVNGGGNVTEKLDLNWYLGIYSGLTVAT
		VLFGIARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRNPIGRILNRFSKDIGHLDDLLPLTFLDF
		IQTLLQVVGVVSVAVAVIPWIAIPLVPLGIIFIFLRRYFLETSRDVKRLESTTRSPVFSHLSSSLQGL
		WTIRAYKAEERCQELFDAHQDLHSEAWFLFLTTSRWFAVRLDAICAMFVIIVAFGSLILAKTLDAGQV
		GLALSYALTLMGMFQWCVRQSAEVENMMISVERVIEYTDLEKEAPWEYQKRPPPAWPHEGVIIFDNVN
		FMYSPGGPLVLKHLTALIKSQEKVGIVGRTGAGKSSLISALFRLSEPEGKIWIDKILTTEIGLHDLRK
		KMSIIPQEPVLFTGTMRKNLDPFNEHTDEELWNALQEVQLKETIEDLPGKMDTELAESGSNFSVGQRQ
		LVCLARAILRKNQILIIDEATANVDPRTDELIQKKIREKFAHCTVLTIAHRLNTIIDSDKIMVLDSGR
		LKEYDEPYVLLQNKESLFYKMVQQLGKAEAAALTETAKQVYFKRNYPHIGHTDHMVTNTSNGQPSTLT
		IFETAL

7163	Human ABCC4	MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEELQGFWDKEV
	isoform 3	LRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEESAKVIQPIFLGKIINYFENYDPMDSVALNTAYA
	(UniProtKB:	YATVLTFCTLILAILHHLYFYHVQCAGMRLRVAMCHMIYRKALRLSNMAMGKTTTGQIVNLLSNDVNK
	O15439-3)	FDQVTVFLHFLWAGPLQAIAVTALLWMEIGISCLAGMAVLIILLPLQSCFGKLFSSLRSKTATFTDAR
		IRTMNEVITGIRIIKMYAWEKSFSNLITNLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYV
		LLGSVITASRVFVAVTLYGAVRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKK
		MVHVQDFTAFWDKASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIA
		YVSQQPWVFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQKARVN
		LARAVYQDADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAASQILILKDGKMV
		QKGTYTEFLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVWSQQSSRPSLKDGALESQDTE
		NVPVTLSEENRSEGKVGFQAYKNYFRAGAHWIVFIFLILLNTAAQVAYVLQDWWLSYWANKQSMLNVT
		VNGGGNVTEKLDLNWYLGIYSGLTVATVLFGIARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRN
		PIGRILNRFSKDIGHLDDLLPLTFLDFIQRWDLAVLSWLVSNS

7164	Human ABCC4	MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEELQGFWDKEV
	isoform 4	LRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEALRLSNMAMGKTTTGQIVNLLSNDVNKFDQVTVF
	(UniProtKB:	LHFLWAGPLQAIAVTALLWMEIGISCLAGMAVLIILLPLQSCFGKLFSSLRSKTATFTDARIRTMNEV
	O15439-4)	ITGIRIIKMYAWEKSFSNLITNLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYVLLGSVIT
		ASRVFVAVTLYGAVRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKKMVHVQDF
		TAFWDKASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIAYVSQQPW
		VFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQKARVNLARAVYQ
		DADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAASQILILKDGKMVQKGTYTE
		FLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVWSQQSSRPSLKDGALESQDTENVPVTLS
		EENRSEGKVGFQAYKNYFRAGAHWIVFIFLILLNTAAQVAYVLQDWWLSYWANKQSMLNVTVNGGGNV
		TEKLDLNWYLGIYSGLTVATVLFGIARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRNPIGRILN
		RFSKDIGHLDDLLPLTFLDFIQRWDLAVLSWLVSNS

7165	Human PAK3	MSDGLDNEEKPPAPPLRMNSNNRDSSALNHSSKPLPMAPEEKNKKARLRSIFPGGGDKTNKKKEKERP
	isoform 1	EISLPSDFEHTIHVGFDAVTGEFTPDLYGSQMCPGKLPEGIPEQWARLLQTSNITKLEQKKNPQAVLD
	(UniProtKB:	VLKFYDSKETVNNQKYMSFTSGDKSAHGYIAAHPSSTKTASEPPLAPPVSEEEDEEEEEEEDENEPPP
	075914-1, v2)	VIAPRPEHTKSIYTRSWESIASPAVPNKEVTPPSAENANSSTLYRNTDRQRKKSKMTDEEILEKLRS
		IVSVGDPKKKYTRFEKIGQGASGTVYTALDIATGQEVAIKQMNLQQQPKKELIINEILVMRENKNPNI
		VNYLDSYLVGDELWVVMEYLAGGSLTDVVTETCMDEGQIAAVCRECLQALDFLHSNQVIHRDIKSDNI
		LLGMDGSVKLTDFGFCAQITPEQSKRSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMVEGEPP
		YLNENPLRALYLIATNGTPELQNPERLSAVFRDFLNRCLEMDVDRRGSAKELLQHPFLKLAKPLSSLT
		PLIIAAKEAIKNSSR

7166	Human PAK3	MSDGLDNEEKPPAPPLRMNSNNRDSSALNHSSKPLPMAPEEKNKKARLRSIFPGGGDKTNKKKEKERP
	isoform 2	EISLPSDFEHTIHVGFDAVTGEFTGIPEQWARLLQTSNITKLEQKKNPQAVLDVLKFYDSKETVNNQK
	(UniProtKB:	YMSFTSGDKSAHGYIAAHPSSTKTASEPPLAPPVSEEEDEEEEEEEDENEPPPVIAPRPEHTKSIYTR
	075914-2)	SVVESIASPAVPNKEVTPPSAENANSSTLYRNTDRQRKKSKMTDEEILEKLRSIVSVGDPKKKYTRFE
		KIGQGASGTVYTALDIATGQEVAIKQMNLQQQPKKELIINEILVMRENKNPNIVNYLDSYLVGDELWV
		VMEYLAGGSLTDVVTETCMDEGQIAAVCRECLQALDFLHSNQVIHRDIKSDNILLGMDGSVKLTDFGF
		CAQITPEQSKRSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMVEGEPPYLNENPLRALYLIAT
		NGTPELQNPERLSAVFRDFLNRCLEMDVDRRGSAKELLQHPFLKLAKPLSSLTPLIIAAKEAIKNSSR

7167	Human PAK3	MSDGLDNEEKPPAPPLRMNSNNRDSSALNHSSKPLPMAPEEKNKKARLRSIFPGGGDKTNKKKEKERP
	isoform 3	EISLPSDFEHTIHVGFDAVTGEFTNSPFQTSRPVTVASSQSEGKMPDLYGSQMCPGKLPEGIPEQWAR
	(UniProtKB:	LLQTSNITKLEQKKNPQAVLDVLKFYDSKETVNNQKYMSFTSGDKSAHGYIAAHPSSTKTASEPPLAP
	075914-3)	PVSEEEDEEEEEEEDENEPPPVIAPRPEHTKSIYTRSVVESIASPAVPNKEVTPPSAENANSSTLYRN
		TDRQRKKSKMTDEEILEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTALDIATGQEVAIKQMNLQQQ
		PKKELIINEILVMRENKNPNIVNYLDSYLVGDELWVVMEYLAGGSLTDVVTETCMDEGQIAAVCRECL
		QALDFLHSNQVIHRDIKSDNILLGMDGSVKLTDFGFCAQITPEQSKRSTMVGTPYWMAPEVVTRKAYG
		PKVDIWSLGIMAIEMVEGEPPYLNENPLRALYLIATNGTPELQNPERLSAVFRDFLNRCLEMDVDRRG
		SAKELLQHPFLKLAKPLSSLTPLIIAAKEAIKNSSR

7168	Human PAK3	MSDGLDNEEKPPAPPLRMNSNNRDSSALNHSSKPLPMAPEEKNKKARLRSIFPGGGDKTNKKKEKERP
	isoform 4	EISLPSDFEHTIHVGFDAVTGEFTNSPFQTSRPVTVASSQSEGKMGIPEQWARLLQTSNITKLEQKKN
	(UniProtKB:	PQAVLDVLKFYDSKETVNNQKYMSFTSGDKSAHGYIAAHPSSTKTASEPPLAPPVSEEEDEEEEEEED
	075914-4)	ENEPPPVIAPRPEHTKSIYTRSVVESIASPAVPNKEVTPPSAENANSSTLYRNTDRQRKKSKMTDEEI
		LEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTALDIATGQEVAIKQMNLQQQPKKELIINEILVMRE
		NKNPNIVNYLDSYLVGDELWVVMEYLAGGSLTDVVTETCMDEGQIAAVCRECLQALDFLHSNQVIHRD
		IKSDNILLGMDGSVKLTDFGFCAQITPEQSKRSTMVGTPYWMAPEWTRKAYGPKVDIWSLGIMAIEM
		VEGEPPYLNENPLRALYLIATNGTPELQNPERLSAVFRDFLNRCLEMDVDRRGSAKELLQHPFLKLAK
		PLSSLTPLIIAAKEAIKNSSR

7169	Human TRNP1	MPGCRISACGPGAQEGTAEQRSPPPPWDPMPSSQPPPPTPTLTPTPTPGQSPPLPDAAGASAGAAEDQ
	(UniProtKB:	ELQRWRQGASGIAGLAGPGGGSGAAAGAGGRALELAEARRRLLEVEGRRRLVSELESRVLQLHRVFLA
	Q6NT89-1, v2)	AELRLAHRAESLSRLSGGVAQAELYLAAHGSRLKKGPRRGRRGRPPALLASALGLGGCVPWGAGRLRR
		GHGPEPDSPFRRSPPRGPASPQR

7170	Human APLN	MNLRLCVQALLLLWLSLTAVCGGSLMPLPDGNGLEDGNVRHLVQPRGSRNGPGPWQGGRRKFRRQRPR
	(UniProtKB:	LSHKGPMPF
	Q9ULZ1-1, v1)

7171	Apelin-36	LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF
	(UniProtKB:
	Q9ULZ1-1, v1
	positions 42-77)

7172	Apelin-31	GSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF
	(UniProtKB:
	Q9ULZ1-1, v1
	positions 47-77)

7173	Apelin-28	NGPGPWQGGRRKFRRQRPRLSHKGPMPF
	(UniProtKB:
	Q9ULZ1-1, v1
	positions 50-77)

7174	Apelin-13	QRPRLSHKGPMPF
	(UniProtKB:
	Q9ULZ1-1, v1
	positions 65-77)

7175	Human KIF20A	MSQGILSPPAGLLSDDDVVVSPMFESTAADLGSVVRKNLLSDCSVVSTSLEDKQQVPSEDSMEKVKVY
	isoform 1	LRVRPLLPSELERQEDQGCVRIENVETLVLQAPKDSFALKSNERGIGQATHRFTFSQIFGPEVGQASF
	(UniProtKB:	FNLTVKEMVKDVLKGQNWLIYTYGVTNSGKTHTIQGTIKDGGILPRSLALIFNSLQGQLHPTPDLKPL
	095235-1, v1)	LSNEVIWLDSKQIRQEEMKKLSLLNGGLQEEELSTSLKRSVYIESRIGTSTSFDSGIAGLSSISQCTS
		SSQLDETSHRWAQPDTAPLPVPANIRFSIWISFFEIYNELLYDLLEPPSQQRKRQTLRLCEDQNGNPY
		VKDLNWIHVQDAEEAWKLLKVGRKNQSFASTHLNQNSSRSHSIFSIRILHLQGEGDIVPKISELSLCD
		LAGSERCKDQKSGERLKEAGNINTSLHTLGRCIAALRQNQQNRSKQNLVPFRDSKLTRVFQGFFTGRG
		RSCMIVNVNPCASTYDETLHVAKFSAIASQLVHAPPMQLGFPSLHSFIKEHSLQVSPSLEKGAKADTG
		LDDDIENEADISMYGKEELLQVVEAMKTLLLKERQEKLQLEMHLRDEICNEMVEQMQQREQWCSEHLD
		TQKELLEEMYEEKLNILKESLTSFYQEEIQERDEKIEELEALLQEARQQSVAHQQSGSELALRRSQRL
		AASASTQQLQEVKAKLQQCKAELNSTTEELHKYQKMLEPPPSAKPFTIDVDKKLEEGQKNIRLLRTEL
		QKLGESLQSAERACCHSTGAGKLRQALTTCDDILIKQDQTLAELQNNMVLVKLDLRKKAACIAEQYHT
		VLKLQGQVSAKKRLGTNQENQQPNQQPPGKKPFLRNLLPRTPTCQSSTDCSPYARILRSRRSPLLKSG
		PFGKKY


7176	Human KIF20A	MSQGILSPPAGLLSDDDVVVSPMFESTAADLGSVVRKNLLSDCSVVSTSLEDKQQVPSEDSMEKEDQG
	isoform 2	CVRIENVETLVLQAPKDSFALKSNERGIGQATHRFTFSQIFGPEVGQASFFNLTVKEMVKDVLKGQNW
	(UniProtKB:	LIYTYGVTNSGKTHTIQGTIKDGGILPRSLALIFNSLQGQLHPTPDLKPLLSNEVIWLDSKQIRQEEM
	095235-2)	KKLSLLNGGLQEEELSTSLKRSVYIESRIGTSTSFDSGIAGLSSISQCTSSSQLDETSHRWAQPDTAP
		LPVPANIRFSIWISFFEIYNELLYDLLEPPSQQRKRQTLRLCEDQNGNPYVKDLNWIHVQDAEEAWKL
		LKVGRKNQSFASTHLNQNSSRSHSIFSIRILHLQGEGDIVPKISELSLCDLAGSERCKDQKSGERLKE
		AGNINTSLHTLGRCIAALRQNQQNRSKQNLVPFRDSKLTRVFQGFFTGRGRSCMIVNVNPCASTYDET
		LHVAKFSAIASQLVHAPPMQLGFPSLHSFIKEHSLQVSPSLEKGAKADTGLDDDIENEADISMYGKEE
		LLQVVEAMKTLLLKERQEKLQLEMHLRDEICNEMVEQMQQREQWCSEHLDTQKELLEEMYEEKLNILK
		ESLTSFYQEEIQERDEKIEELEALLQEARQQSVAHQQSGSELALRRSQRLAASASTQQLQEVKAKLQQ
		CKAELNSTTEELHKYQKMLEPPPSAKPFTIDVDKKLEEGQKNIRLLRTELQKLGESLQSAERACCHST
		GAGKLRQALTTCDDILIKQDQTLAELQNNMVLVKLDLRKKAACIAEQYHTVLKLQGQVSAKKRLGTNQ
		ENQQPNQQPPGKKPFLRNLLPRTPTCQSSTDCSPYARILRSRRSPLLKSGPFGKKY
7177	Human LTB	MGALGLEGRGGRLQGRGSLLLAVAGATSLVTLLLAVPITVLAVLALVPQDQGGLVTETADPGAQAQQG
	isoform 1	LGFQKLPEEEPETDLSPGLPAAHLIGAPLKGQGLGWETTKEQAFLTSGTQFSDAEGLALPQDGLYYLY
	(UniProtKB:	CLVGYRGRAPPGGGDPQGRSVTLRSSLYRAGGAYGPGTPELLLEGAETVTPVLDPARRQGYGPLWYTS
	Q06643-1, v1)	VGFGGLVQLRRGERVYVNISHPDMVDFARGKTFFGAVMVG

7178	Human LTB	MGALGLEGRGGRLQGRGSLLLAVAGATSLVTLLLAVPITVLAVLALVPQDQGGLGFRSCQRRSQKQIS
	isoform 2	APGSQLPTS
	(UniProtKB:
	Q06643-2)

7179	Human MFAP4	GCAGACACCCAGCCACTCTGAGCAGAACTGACAGCATGAAGGTACGGGGCCCAGGGTCGGGGGACTCA
	transcript	TAGCATGGGGGAACTGAGCCCACTCCAGAGGCCCCTGGCCACAGAGGGCACTATGAAGGCACAAGGAG
	variant 1 mRNA	TTCTCTTGAAACTCGCACTCCTGGCCCTGCCGCTGCTGCTGCTTCTCTCCACGCCCCCGTGTGCCCCC
	NM_001198695.	CAGGTCTCCGGGATCCGAGGAGATGCTCTGGAGAGGTTTTGCCTTCAGCAACCCCTGGACTGTGACGA
	2	CATCTATGCCCAGGGCTACCAGTCAGACGGCGTGTACCTCATCTACCCCTCGGGCCCCAGTGTGCCTG
	(GI:1677501926	TGCCCGTCTTCTGTGACATGACCACCGAGGGCGGGAAGTGGACGGTTTTCCAGAAGAGATTCAATGGC
	version 2)	TCAGTAAGTTTCTTCCGCGGCTGGAATGACTACAAGCTGGGCTTCGGCCGTGCTGATGGAGAGTACTG
		GCTGGGGCTGCAGAACATGCACCTCCTGACACTGAAGCAGAAGTATGAGCTGCGAGTGGACTTGGAGG
		ACTTTGAGAACAACACGGCCTATGCCAAGTACGCTGACTTCTCCATCTCCCCGAACGCGGTCAGCGCA
		GAGGAGGATGGCTACACCCTCTTTGTGGCAGGCTTTGAGGATGGCGGGGCAGGTGACTCCCTGTCCTA
		CCACAGTGGCCAGAAGTTCTCTACCTTCGACCGGGACCAGGACCTCTTTGTGCAGAACTGCGCAGCTC
		TCTCCTCAGGAGCCTTCTGGTTCCGCAGCTGCCACTTTGCCAACCTCAATGGCTTCTACCTAGGTGGC
		TCCCACCTCTCTTATGCCAATGGCATCAACTGGGCCCAGTGGAAGGGCTTCTACTACTCCCTCAAACG
		CACTGAGATGAAAATCCGCCGGGCCTGAAGGGCTGGCCCCCTCAGGCACCTTTCCTCCCCTGGACACC
		CATGGTCTCCATGAGTGCTCCCTCTGCTGCCCCTGATGCATGCTTCTGCTGATTCCCGAGCACCAACT
		CCTTACAAGGGGGCCTTGTGGCTCTCAGCCATGCCACATCCCTGTCACACACCCAGGGCATCCATTCC
		TAAGCCAGACCCGGCTCCCCTACACCTGAAGTTACACTGCCAGCAGTTCCCCAGGCCTCTTCCGAGAG
		GCACATGGTTCTAGCCTGGACCTGGCTGGGCTCCATGAGAATGAGTTGCCTCCAACCTGTCCCAACAG
		CTGACAGCCAGGAGCCACTCTCCCAGCTGCAGGCCTTTGTGGTCCATCTTGTCCTGCTTCCTCACTGT
		GGACCCCTGTCTGGGCCACCCTAGTGTGCTAAGCTGAGCAGTGCAGTGTGAACAGGGCCCATGGTGTA
		TTCTAGGCCACAGCCCAGCACTCCTCTGGGCTGCTCTCAAACCATGTCCCATCTTCAGCATCCCTCCC
		ACCAACTTACTCCCCTGTGGTGAGTACCGTGGAACCCCAGCCCACCTCACTATCATACTCAGCTTCCC
		CTGATGGCCCATCCCAGCCCCTGAAGCTCTATGCCAAGAACACAGCTACCGCACACCACCCTGAAACA
		GCCACAGCCAAGGTAGGCATGCATATGAGGTCTTCCCCATACCCTCTGGGTGTTGAGAGGTTTAGCCA
		CATGAGGGAGCAGAGGACAATCTCTGCAGGGCTGGGAGTGGGTAGGGACTGAAGGTCTCAATAAACCT
		TCAGAACCTGAATGAACTGGCTTCATACACACAAACATATTTGTTTATCCCCCAAATGTAGGCACCTG
		GCTCCTCCTTGCTCCCCTGCTGATGGTGTCCTACCCCGAACTCCAAAAATTACACCTGGAGTCAGGTG
		CAGAAGGGAACCTTGTATTTCACAGGCCTCATTTTGATGGCAAAAAGACAGTGTAATAATAACATAAT
		AATAATAAAAATATAATACTGAAAA

7180	Human MFAP4	GCAGACACCCAGCCACTCTGAGCAGAACTGACAGCATGAAGGCACTCCTGGCCCTGCCGCTGCTGCTG
	transcript	CTTCTCTCCACGCCCCCGTGTGCCCCCCAGGTCTCCGGGATCCGAGGAGATGCTCTGGAGAGGTTTTG
	variant	CCTTCAGCAACCCCTGGACTGTGACGACATCTATGCCCAGGGCTACCAGTCAGACGGCGTGTACCTCA
	2 mRNA	TCTACCCCTCGGGCCCCAGTGTGCCTGTGCCCGTCTTCTGTGACATGACCACCGAGGGCGGGAAGTGG
	NM_002404.3	ACGGTTTTCCAGAAGAGATTCAATGGCTCAGTAAGTTTCTTCCGCGGCTGGAATGACTACAAGCTGGG
	(GI:1677501522	CTTCGGCCGTGCTGATGGAGAGTACTGGCTGGGGCTGCAGAACATGCACCTCCTGACACTGAAGCAGA
	version 3)	AGTATGAGCTGCGAGTGGACTTGGAGGACTTTGAGAACAACACGGCCTATGCCAAGTACGCTGACTTC
		TCCATCTCCCCGAACGCGGTCAGCGCAGAGGAGGATGGCTACACCCTCTTTGTGGCAGGCTTTGAGGA
		TGGCGGGGCAGGTGACTCCCTGTCCTACCACAGTGGCCAGAAGTTCTCTACCTTCGACCGGGACCAGG
		ACCTCTTTGTGCAGAACTGCGCAGCTCTCTCCTCAGGAGCCTTCTGGTTCCGCAGCTGCCACTTTGCC
		AACCTCAATGGCTTCTACCTAGGTGGCTCCCACCTCTCTTATGCCAATGGCATCAACTGGGCCCAGTG
		GAAGGGCTTCTACTACTCCCTCAAACGCACTGAGATGAAAATCCGCCGGGCCTGAAGGGCTGGCCCCC
		TCAGGCACCTTTCCTCCCCTGGACACCCATGGTCTCCATGAGTGCTCCCTCTGCTGCCCCTGATGCAT
		GCTTCTGCTGATTCCCGAGCACCAACTCCTTACAAGGGGGCCTTGTGGCTCTCAGCCATGCCACATCC
		CTGTCACACACCCAGGGCATCCATTCCTAAGCCAGACCCGGCTCCCCTACACCTGAAGTTACACTGCC
		AGCAGTTCCCCAGGCCTCTTCCGAGAGGCACATGGTTCTAGCCTGGACCTGGCTGGGCTCCATGAGAA
		TGAGTTGCCTCCAACCTGTCCCAACAGCTGACAGCCAGGAGCCACTCTCCCAGCTGCAGGCCTTTGTG
		GTCCATCTTGTCCTGCTTCCTCACTGTGGACCCCTGTCTGGGCCACCCTAGTGTGCTAAGCTGAGCAG
		TGCAGTGTGAACAGGGCCCATGGTGTATTCTAGGCCACAGCCCAGCACTCCTCTGGGCTGCTCTCAAA
		CCATGTCCCATCTTCAGCATCCCTCCCACCAACTTACTCCCCTGTGGTGAGTACCGTGGAACCCCAGC
		CCACCTCACTATCATACTCAGCTTCCCCTGATGGCCCATCCCAGCCCCTGAAGCTCTATGCCAAGAAC
		ACAGCTACCGCACACCACCCTGAAACAGCCACAGCCAAGGTAGGCATGCATATGAGGTCTTCCCCATA
		CCCTCTGGGTGTTGAGAGGTTTAGCCACATGAGGGAGCAGAGGACAATCTCTGCAGGGCTGGGAGTGG
		GTAGGGACTGAAGGTCTCAATAAACCTTCAGAACCTGAATGAACTGGCTTCATACACACAAACATATT
		TGTTTATCCCCCAAATGTAGGCACCTGGCTCCTCCTTGCTCCCCTGCTGATGGTGTCCTACCCCGAAC
		TCCAAAAATTACACCTGGAGTCAGGTGCAGAAGGGAACCTTGTATTTCACAGGCCTCATTTTGATGGC
		AAAAAGACAGTGTAATAATAACATAATAATAATAAAAATATAATACTGAAAA

7181	Human GRHPR	ACATTCCCGGGCCAGCTTCTGTACTGCCAGGTCCGGGTCGGCGGCTGCACTGCGGATGAGACCGGTGC
	transcript	GACTCATGAAGGTGTTCGTCACCCGCAGGATACCCGCCGAGGGTAGGGTCGCGCTCGCCCGGGCGGCA
	variant	GACTGTGAGGTGGAGCAGTGGGACTCGGATGAGCCCATCCCTGCCAAGGAGCTAGAGCGAGGTGTGGC
	1 mRNA	GGGGGCCCACGGCCTGCTCTGCCTCCTCTCCGACCACGTGGACAAGAGGATCCTGGATGCTGCAGGGG
	NM_012203.2	CCAATCTCAAAGTCATCAGCACCATGTCTGTGGGCATCGACCACTTGGCTTTGGATGAAATCAAGAAG
	(GI:1519473711	CGTGGGATCCGAGTTGGCTACACCCCAGATGTCCTGACAGATACCACCGCCGAACTCGCAGTCTCCCT
	version 2)	GCTACTTACCACCTGCCGCCGGTTGCCGGAGGCCATCGAGGAAGTGAAGAATGGTGGCTGGACCTCGT
		GGAAGCCCCTCTGGCTGTGTGGCTATGGACTCACGCAGAGCACTGTCGGCATCATCGGGCTGGGGCGC
		ATAGGCCAGGCCATTGCTCGGCGTCTGAAACCATTCGGTGTCCAGAGATTTCTGTACACAGGGCGCCA
		GCCCAGGCCTGAGGAAGCAGCAGAATTCCAGGCAGAGTTTGTGTCTACCCCTGAGCTGGCTGCCCAAT
		CTGATTTCATCGTCGTGGCCTGCTCCTTAACACCTGCAACCGAGGGACTCTGCAACAAGGACTTCTTC
		CAGAAGATGAAGGAAACAGCTGTGTTCATCAACATCAGCAGGGGCGACGTCGTAAACCAGGACGACCT
		GTACCAGGCCTTGGCCAGTGGTAAGATTGCAGCTGCTGGACTGGATGTGACGAGCCCAGAACCACTGC
		CTACAAACCACCCTCTCCTGACCCTGAAGAACTGTGTGATTCTGCCCCACATTGGCAGTGCCACCCAC
		AGAACCCGCAACACCATGTCCTTGTTGGCAGCTAACAACTTGCTGGCTGGCCTGAGAGGGGAGCCGAT
		GCCTAGTGAACTCAAGCTGTAGCCAAACAGTAGAGATGGAGGGCCGGGAAGCAAACCGTGCCCTGGTA
		TTGTCAGACACACCCAGGCTTGATTTGGATCCACAGGCAGAGCCAAGGGAAGGTGTGATTCTCTGAGG
		AAAGAGTGATTCTGATATATGTACTTGTCACATTGGTGTTGGACACATTTGCGCCAAAAGTATGGTAA
		TTCTATTATTAAATAATTCTCTGAGA

7182	Human ITFG1	GGGGGCTGAGGGGCTGCCATGGCGGCGGCGGGCCGGCTCCCGAGCTCCTGGGCCCTCTTCTCGCCGCT
	transcript	CCTCGCAGGGCTTGCACTACTGGGAGTCGGGCCGGTCCCAGCGCGGGCGCTGCACAACGTCACGGCCG
	variant	AGCTCTTTGGGGCCGAGGCCTGGGGCACCCTTGCGGCTTTCGGGGACCTCAACTCCGACAAGCAGACG
	1 mRNA	GATCTCTTCGTGCTGCGGGAAAGAAATGACTTAATCGTCTTTTTGGCAGACCAGAATGCACCCTATTT
	NM_030790.5	TAAACCCAAAGTAAAGGTATCTTTCAAGAATCACAGTGCATTGATAACAAGTGTAGTCCCTGGGGATT
	(GI:1653961895	ATGATGGAGATTCTCAAATGGATGTCCTTCTGACATATCTTCCCAAAAATTATGCCAAGAGTGAATTA
	version 5)	GGAGCTGTTATCTTCTGGGGACAAAATCAAACATTAGATCCTAACAATATGACCATACTCAATAGGAC
		TTTTCAAGATGAGCCACTAATTATGGATTTCAATGGTGATCTAATTCCTGATATTTTTGGTATCACAA
		ATGAATCCAACCAGCCACAGATACTATTAGGAGGGAATTTATCATGGCATCCAGCATTGACCACTACA
		AGTAAAATGCGAATTCCACATTCTCATGCATTTATTGATCTGACTGAAGATTTTACAGCAGATTTATT
		CCTGACGACATTGAATGCCACCACTAGTACCTTCCAGTTTGAAATATGGGAAAATTTGGATGGAAACT
		TCTCTGTCAGTACTATATTGGAAAAACCTCAAAATATGATGGTGGTTGGACAGTCAGCATTTGCAGAC
		TTTGATGGAGATGGACACATGGATCATTTACTGCCAGGCTGTGAAGATAAAAATTGCCAAAAGAGTAC
		CATCTACTTAGTGAGATCTGGGATGAAGCAGTGGGTTCCAGTCCTACAAGATTTCAGCAATAAGGGCA
		CACTCTGGGGCTTTGTGCCATTTGTGGATGAACAGCAACCAACTGAAATACCAATTCCAATTACCCTT
		CATATTGGAGACTACAATATGGATGGCTATCCAGACGCTCTGGTCATACTAAAGAACACATCTGGAAG
		CAACCAGCAGGCCTTTTTACTGGAGAACGTCCCTTGTAATAATGCAAGCTGTGAAGAGGCGCGTCGAA
		TGTTTAAAGTCTACTGGGAGCTGACAGACCTAAATCAAATTAAGGATGCCATGGTTGCCACCTTCTTT
		GACATTTACGAAGATGGAATCTTGGACATTGTAGTGCTAAGTAAAGGATATACAAAGAATGATTTTGC
		CATTCATACACTAAAAAATAACTTTGAAGCAGATGCTTATTTTGTTAAAGTTATTGTTCTTAGTGGTC
		TGTGTTCTAATGACTGTCCTCGTAAGATAACACCCTTTGGAGTGAATCAACCTGGACCTTATATCATG
		TATACAACTGTAGATGCAAATGGGTATCTGAAAAATGGATCAGCTGGCCAACTCAGCCAATCCGCACA
		TTTAGCTCTCCAACTACCATACAACGTGCTTGGTTTAGGTCGGAGCGCAAATTTTCTTGACCATCTCT
		ACGTTGGTATTCCCCGTCCATCTGGAGAAAAATCTATACGAAAACAAGAGTGGACTGCAATCATTCCA
		AATTCCCAGCTAATTGTCATTCCATACCCTCACAATGTCCCTCGAAGTTGGAGTGCCAAACTGTATCT
		TACACCAAGTAATATTGTTCTGCTTACTGCTATAGCTCTCATCGGTGTCTGTGTTTTCATCTTGGCAA
		TAATTGGCATTTTACATTGGCAGGAAAAGAAAGCAGATGATAGAGAAAAACGACAAGAAGCCCACCGG
		TTTCATTTTGATGCTATGTGACTTGCCTTTAATATTACATAATGGAATGGCTGTTCACTTGATTAGTT
		GAAACACAAATTCTGGCTTGAAAAAATAGGGGAGATTAAATATTATTTATAAATGATGTATCCCATGG
		TAATTATTGGAAAGTATTCAAATAAATATGGTTTGAATATGTCACAAGGTCTTTTTTTTTAAAGCACT
		TTGTATATAAAAATTTGGGTTCTCTATTCTGTAGTGCTGTACATTTTTGTTCCTTTGTGGAATGTGTT
		GCATGTACTCCAGTGTTTGTGTATTTATAATCTTATTTGCATCATGATGATGGAAAAAGTTGTGTAAA
		TAAAAATAATTAAATGAGCAGGAATTTTTGTGTCCACTTGACTTGGTCTTGCTTCTTATTCTAATGAT
		GCAAATTATACTTTTGTGAATATATCACGGAGTCATTAGGCATTCAGCTTCATCACAGCAGGTCAGGG
		GTCTCACTGATGGCATACAATATAGTGATCGGGTACTCTGACTTGGTAGCACAGTAAGACAGACTTGC
		CTTAAACTCCTAATTCAACCACTTACAAAGTCATTGTTTGAACTTGGCTCTTGTTTAACCTCTGTAAA
		CCTCAGTTTTCTTGTTTATTCAGTGGGGCTAATACTTGAGTTACTGTAAACATTAAATGGGATGATGT
		ATGTGAAGTGCTTAGCTTGGTGCCTAGCACAGAGTAAGTGGTCAATATGTGGTAGTTGTCATTATTAA
		TATTTTAGATGATCTTATTAGACTTATACATCTAATTATAGAAATACATAGACTTGATAGAATTTTAT
		TTTCAGGCATGAAGAAATATTCTTTGGAAAAGCTAAATTTTTGGTGATTGACATAAAGATTTACTTGC
		TCATATTAACTAAAAATTATAGTACTCTCCAAGAATTAATGTGCCCTAAAAATTTTCCTCCAAAAACT
		TATCCTTATCATGTGATAATGAAGAACATTTGATTTCTTGAAAGGAAACTGCTGTAGGCAGCATCTGG
		GAATGCAAATCTTCAATCACATTTCTATTCTCAAACACTTGGAGAAGTCTATAATTTACATTCAGACT
		TCAATGCAAATTTTGTATTGTGAACTTCACATTTCCAAAAAGTTACTTTAAAAAGACTTTAAGACTGA
		AAAAAAAAAGTTTATCAATGCTAATAATTTTCTAGTATGCAAATGGACATGTGATGCCTATAAAACAC
		AAAAATTTCTCTGAAAACAATTTTGTTCTTATTTTTTTCTTTATAGTTCACTGAGATTGGCATGTGTT
		TTTACTTTGTATCTAAGCATGTTAACATGTCTTCTTAATAAATATTCCTTATTGAAA

7183	Human ABCC4	GCTTCACAGGCTCCAGCCGAGCGGACAGGCGTGGCGGCCGGAGCCCCAGCATCCCTGCTTGAGGTCCA
	transcript	GGAGCGGAGCCCGCGGCCACCGCCGCCTGATCAGCGCGACCCCGGCCCGCGCCCGCCCCGCCCGGCAA
	variant	GATGCTGCCCGTGTACCAGGAGGTGAAGCCCAACCCGCTGCAGGACGCGAACCTCTGCTCACGCGTGT
	1 mRNA	TCTTCTGGTGGCTCAATCCCTTGTTTAAAATTGGCCATAAACGGAGATTAGAGGAAGATGATATGTAT
	NM_005845.5	TCAGTGCTGCCAGAAGACCGCTCACAGCACCTTGGAGAGGAGTTGCAAGGGTTCTGGGATAAAGAAGT
	(GI:1813751621	TTTAAGAGCTGAGAATGACGCACAGAAGCCTTCTTTAACAAGAGCAATCATAAAGTGTTACTGGAAAT
	version 5)	CTTATTTAGTTTTGGGAATTTTTACGTTAATTGAGGAAAGTGCCAAAGTAATCCAGCCCATATTTTTG
		GGAAAAATTATTAATTATTTTGAAAATTATGATCCCATGGATTCTGTGGCTTTGAACACAGCGTACGC
		CTATGCCACGGTGCTGACTTTTTGCACGCTCATTTTGGCTATACTGCATCACTTATATTTTTATCACG
		TTCAGTGTGCTGGGATGAGGTTACGAGTAGCCATGTGCCATATGATTTATCGGAAGGCACTTCGTCTT
		AGTAACATGGCCATGGGGAAGACAACCACAGGCCAGATAGTCAATCTGCTGTCCAATGATGTGAACAA
		GTTTGATCAGGTGACAGTGTTCTTACACTTCCTGTGGGCAGGACCACTGCAGGCGATTGCAGTGACTG
		CCCTACTCTGGATGGAGATAGGAATATCGTGCCTTGCTGGGATGGCAGTTCTAATCATTCTCCTGCCC
		TTGCAAAGCTGTTTTGGGAAGTTGTTCTCATCACTGAGGAGTAAAACTGCAACTTTCACGGATGCCAG
		GATCAGGACCATGAATGAAGTTATAACTGGTATAAGGATAATAAAAATGTACGCCTGGGAAAAGTCAT
		TTTCAAATCTTATTACCAATTTGAGAAAGAAGGAGATTTCCAAGATTCTGAGAAGTTCCTGCCTCAGA
		GGGATGAATTTGGCTTCATTTTTCAGTGCAAGCAAAATCATCGTGTTTGTGACCTTCACCACCTACGT
		GCTCCTCGGCAGTGTGATCACAGCCAGCCGCGTGTTCGTGGCAGTGACGCTGTATGGGGCTGTGCGGC
		TGACGGTTACCCTCTTCTTCCCCTCAGCCATTGAGAGGGTGTCAGAGGCAATCGTCAGCATCCGAAGA
		ATCCAGACCTTTTTGCTACTTGATGAGATATCACAGCGCAACCGTCAGCTGCCGTCAGATGGTAAAAA
		GATGGTGCATGTGCAGGATTTTACTGCTTTTTGGGATAAGGCATCAGAGACCCCAACTCTACAAGGCC
		TTTCCTTTACTGTCAGACCTGGCGAATTGTTAGCTGTGGTCGGCCCCGTGGGAGCAGGGAAGTCATCA
		CTGTTAAGTGCCGTGCTCGGGGAATTGGCCCCAAGTCACGGGCTGGTCAGCGTGCATGGAAGAATTGC
		CTATGTGTCTCAGCAGCCCTGGGTGTTCTCGGGAACTCTGAGGAGTAATATTTTATTTGGGAAGAAAT
		ACGAAAAGGAACGATATGAAAAAGTCATAAAGGCTTGTGCTCTGAAAAAGGATTTACAGCTGTTGGAG
		GATGGTGATCTGACTGTGATAGGAGATCGGGGAACCACGCTGAGTGGAGGGCAGAAAGCACGGGTAAA
		CCTTGCAAGAGCAGTGTATCAAGATGCTGACATCTATCTCCTGGACGATCCTCTCAGTGCAGTAGATG
		CGGAAGTTAGCAGACACTTGTTCGAACTGTGTATTTGTCAAATTTTGCATGAGAAGATCACAATTTTA
		GTGACTCATCAGTTGCAGTACCTCAAAGCTGCAAGTCAGATTCTGATATTGAAAGATGGTAAAATGGT
		GCAGAAGGGGACTTACACTGAGTTCCTAAAATCTGGTATAGATTTTGGCTCCCTTTTAAAGAAGGATA
		ATGAGGAAAGTGAACAACCTCCAGTTCCAGGAACTCCCACACTAAGGAATCGTACCTTCTCAGAGTCT
		TCGGTTTGGTCTCAACAATCTTCTAGACCCTCCTTGAAAGATGGTGCTCTGGAGAGCCAAGATACAGA
		GAATGTCCCAGTTACACTATCAGAGGAGAACCGTTCTGAAGGAAAAGTTGGTTTTCAGGCCTATAAGA
		ATTACTTCAGAGCTGGTGCTCACTGGATTGTCTTCATTTTCCTTATTCTCCTAAACACTGCAGCTCAG
		GTTGCCTATGTGCTTCAAGATTGGTGGCTTTCATACTGGGCAAACAAACAAAGTATGCTAAATGTCAC
		TGTAAATGGAGGAGGAAATGTAACCGAGAAGCTAGATCTTAACTGGTACTTAGGAATTTATTCAGGTT
		TAACTGTAGCTACCGTTCTTTTTGGCATAGCAAGATCTCTATTGGTATTCTACGTCCTTGTTAACTCT
		TCACAAACTTTGCACAACAAAATGTTTGAGTCAATTCTGAAAGCTCCGGTATTATTCTTTGATAGAAA
		TCCAATAGGAAGAATTTTAAATCGTTTCTCCAAAGACATTGGACACTTGGATGATTTGCTGCCGCTGA
		CGTTTTTAGATTTCATCCAGACATTGCTACAAGTGGTTGGTGTGGTCTCTGTGGCTGTGGCCGTGATT
		CCTTGGATCGCAATACCCTTGGTTCCCCTTGGAATCATTTTCATTTTTCTTCGGCGATATTTTTTGGA
		AACGTCAAGAGATGTGAAGCGCCTGGAATCTACAACTCGGAGTCCAGTGTTTTCCCACTTATCATCTT
		CTCTCCAGGGGCTCTGGACCATCCGGGCATACAAAGCAGAAGAGAGGTGTCAGGAACTGTTTGATGCA
		CACCAGGATTTACATTCAGAGGCTTGGTTCTTGTTTTTGACAACGTCCCGCTGGTTTGCCGTCCGTCT
		GGATGCCATCTGTGCCATGTTTGTCATCATCGTTGCCTTTGGGTCCCTGATTCTGGCAAAAACTCTGG
		ATGCCGGGCAGGTTGGTTTGGCACTGTCCTATGCCCTCACGCTCATGGGGATGTTTCAGTGGTGTGTT
		CGACAAAGTGCTGAAGTTGAGAATATGATGATCTCAGTAGAAAGGGTCATTGAATACACAGACCTTGA
		AAAAGAAGCACCTTGGGAATATCAGAAACGCCCACCACCAGCCTGGCCCCATGAAGGAGTGATAATCT
		TTGACAATGTGAACTTCATGTACAGTCCAGGTGGGCCTCTGGTACTGAAGCATCTGACAGCACTCATT
		AAATCACAAGAAAAGGTTGGCATTGTGGGAAGAACCGGAGCTGGAAAAAGTTCCCTCATCTCAGCCCT
		TTTTAGATTGTCAGAACCCGAAGGTAAAATTTGGATTGATAAGATCTTGACAACTGAAATTGGACTTC
		ACGATTTAAGGAAGAAGATGTCAATCATACCTCAGGAACCTGTTTTGTTCACTGGAACAATGAGGAAA
		AACCTGGATCCCTTTAATGAGCACACGGATGAGGAACTGTGGAATGCCTTACAAGAGGTACAACTTAA
		AGAAACCATTGAAGATCTTCCTGGTAAAATGGATACTGAATTAGCAGAATCAGGATCCAATTTTAGTG
		TTGGACAAAGACAACTGGTGTGCCTTGCCAGGGCAATTCTCAGGAAAAATCAGATATTGATTATTGAT
		GAAGCGACGGCAAATGTGGATCCAAGAACTGATGAGTTAATACAAAAAAAAATCCGGGAGAAATTTGC
		CCACTGCACCGTGCTAACCATTGCACACAGATTGAACACCATTATTGACAGCGACAAGATAATGGTTT
		TAGATTCAGGAAGACTGAAAGAATATGATGAGCCGTATGTTTTGCTGCAAAATAAAGAGAGCCTATTT
		TACAAGATGGTGCAACAACTGGGCAAGGCAGAAGCCGCTGCCCTCACTGAAACAGCAAAACAGGTATA
		CTTCAAAAGAAATTATCCACATATTGGTCACACTGACCACATGGTTACAAACACTTCCAATGGACAGC
		CCTCGACCTTAACTATTTTCGAGACAGCACTGTGAATCCAACCAAAATGTCAAGTCCGTTCCGAAGGC
		ATTTTCCACTAGTTTTTGGACTATGTAAACCACATTGTACTTTTTTTTACTTTGGCAACAAATATTTA
		TACATACAAGATGCTAGTTCATTTGAATATTTCTCCCAACTTATCCAAGGATCTCCAGCTCTAACAAA
		ATGGTTTATTTTTATTTAAATGTCAATAGTTGTTTTTTAAAATCCAAATCAGAGGTGCAGGCCACCAG
		TTAAATGCCGTCTATCAGGTTTTGTGCCTTAAGAGACTACAGAGTCAAAGCTCATTTTTAAAGGAGTA
		GGACAAAGTTGTCACAGGTTTTTGTTGTTGTTTTTATTGCCCCCAAAATTACATGTTAATTTCCATTT
		ATATCAGGGATTCTATTTACTTGAAGACTGTGAAGTTGCCATTTTGTCTCATTGTTTTCTTTGACATA
		ACTAGGATCCATTATTTCCCCTGAAGGCTTCTTGTTAGAAAATAGTACAGTTACAACCAATAGG
		AACAACAAAAAGAAAAAGTTTGTGACATTGTAGTAGGGAGTGTGTACCCCTTACTCCCCATCAAAAAA
		AAAAATGGATACATGGTTAAAGGATAGAAGGGCAATATTTTATCATATGTTCTAAAAGAGAAGGAAGA
		GAAAATACTACTTTCTCAAAATGGAAGCCCTTAAAGGTGCTTTGATACTGAAGGACACAAATGTGACC
		GTCCATCCTCCTTTAGAGTTGCATGACTTGGACACGGTAACTGTTGCAGTTTTAGACTCAGCATTGTG
		ACACTTCCCAAGAAGGCCAAACCTCTAACCGACATTCCTGAAATACGTGGCATTATTCTTTTTTGGAT
		TTCTCATTTATGGAAGGCTAACCCTCTGTTGACTGTAAGCCTTTTGGTTTGGGCTGTATTGAAATCCT
		TTCTAAATTGCATGAATAGGCTCTGCTAACGTGATGAGACAAACTGAAAATTATTGCAAGCATTGACT
		ATAATTATGCAGTACGTTCTCAGGATGCATCCAGGGGTTCATTTTCATGAGCCTGTCCAGGTTAGTTT
		ACTCCTGACCACTAATAGCATTGTCATTTGGGCTTTCTGTTGAATGAATCAACAAACCACAATACTTC
		CTGGGACCTTTTGTACTTTATTTGAACTATGAGTCTTTAATTTTTCCTGATGATGGTGGCTGTAATAT
		GTTGAGTTCAGTTTACTAAAGGTTTTACTATTATGGTTTGAAGTGGAGTCTCATGACCTCTCAGAATA
		AGGTGTCACCTCCCTGAAATTGCATATATGTATATAGACATGCACACGTGTGCATTTGTTTGTATACA
		TATATTTGTCCTTCGTATAGCAAGTTTTTTGCTCATCAGCAGAGAGCAACAGATGTTTTATTGAGTGA
		AGCCTTAAAAAGCACACACCACACACAGCTAACTGCCAAAATACATTGACCGTAGTAGCTGTTCAACT
		CCTAGTACTTAGAAATACACGTATGGTTAATGTTCAGTCCAACAAACCACACACAGTAAATGTTTATT
		AATAGTCATGGTTCGTATTTTAGGTGACTGAAATTGCATCAGTGATCATAATGAGGTTTGTTAAAACG
		ATAGCTATATTCAAAATGTCTATATGTTTATTTGGACTTTTGAGGTTAAAGACAGTCATATAAACGTC
		CTGTTTCTGTTTTAATGTTATCATAGAATTTTTTAATGAAACTAAATTCAATTGAAATAAATGATAGT
		TTTCATCTCCA

7184	Human ABCC4	GCTTCACAGGCTCCAGCCGAGCGGACAGGCGTGGCGGCCGGAGCCCCAGCATCCCTGCTTGAGGTCCA
	transcript	GGAGCGGAGCCCGCGGCCACCGCCGCCTGATCAGCGCGACCCCGGCCCGCGCCCGCCCCGCCCGGCAA
	variant	GATGCTGCCCGTGTACCAGGAGGTGAAGCCCAACCCGCTGCAGGACGCGAACCTCTGCTCACGCGTGT
	2 mRNA	TCTTCTGGTGGCTCAATCCCTTGTTTAAAATTGGCCATAAACGGAGATTAGAGGAAGATGATATGTAT
	NM_001105515.	TCAGTGCTGCCAGAAGACCGCTCACAGCACCTTGGAGAGGAGTTGCAAGGGTTCTGGGATAAAGAAGT
	3	TTTAAGAGCTGAGAATGACGCACAGAAGCCTTCTTTAACAAGAGCAATCATAAAGTGTTACTGGAAAT
	(GI:1677498821	CTTATTTAGTTTTGGGAATTTTTACGTTAATTGAGGAAAGTGCCAAAGTAATCCAGCCCATATTTTTG
	version 3)	GGAAAAATTATTAATTATTTTGAAAATTATGATCCCATGGATTCTGTGGCTTTGAACACAGCGTACGC
		CTATGCCACGGTGCTGACTTTTTGCACGCTCATTTTGGCTATACTGCATCACTTATATTTTTATCACG
		TTCAGTGTGCTGGGATGAGGTTACGAGTAGCCATGTGCCATATGATTTATCGGAAGGCACTTCGTCTT
		AGTAACATGGCCATGGGGAAGACAACCACAGGCCAGATAGTCAATCTGCTGTCCAATGATGTGAACAA
		GTTTGATCAGGTGACAGTGTTCTTACACTTCCTGTGGGCAGGACCACTGCAGGCGATTGCAGTGACTG
		CCCTACTCTGGATGGAGATAGGAATATCGTGCCTTGCTGGGATGGCAGTTCTAATCATTCTCCTGCCC
		TTGCAAAGCTGTTTTGGGAAGTTGTTCTCATCACTGAGGAGTAAAACTGCAACTTTCACGGATGCCAG
		GATCAGGACCATGAATGAAGTTATAACTGGTATAAGGATAATAAAAATGTACGCCTGGGAAAAGTCAT
		TTTCAAATCTTATTACCAATTTGAGAAAGAAGGAGATTTCCAAGATTCTGAGAAGTTCCTGCCTCAGA
		GGGATGAATTTGGCTTCATTTTTCAGTGCAAGCAAAATCATCGTGTTTGTGACCTTCACCACCTACGT
		GCTCCTCGGCAGTGTGATCACAGCCAGCCGCGTGTTCGTGGCAGTGACGCTGTATGGGGCTGTGCGGC
		TGACGGTTACCCTCTTCTTCCCCTCAGCCATTGAGAGGGTGTCAGAGGCAATCGTCAGCATCCGAAGA
		ATCCAGACCTTTTTGCTACTTGATGAGATATCACAGCGCAACCGTCAGCTGCCGTCAGATGGTAAAAA
		GATGGTGCATGTGCAGGATTTTACTGCTTTTTGGGATAAGGCATCAGAGACCCCAACTCTACAAGGCC
		TTTCCTTTACTGTCAGACCTGGCGAATTGTTAGCTGTGGTCGGCCCCGTGGGAGCAGGGAAGTCATCA
		CTGTTAAGTGCCGTGCTCGGGGAATTGGCCCCAAGTCACGGGCTGGTCAGCGTGCATGGAAGAATTGC
		CTATGTGTCTCAGCAGCCCTGGGTGTTCTCGGGAACTCTGAGGAGTAATATTTTATTTGGGAAGAAAT
		ACGAAAAGGAACGATATGAAAAAGTCATAAAGGCTTGTGCTCTGAAAAAGGATTTACAGCTGTTGGAG
		GATGGTGATCTGACTGTGATAGGAGATCGGGGAACCACGCTGAGTGGAGGGCAGAAAGCACGGGTAAA
		CCTTGCAAGAGCAGTGTATCAAGATGCTGACATCTATCTCCTGGACGATCCTCTCAGTGCAGTAGATG
		CGGAAGTTAGCAGACACTTGTTCGAACTGTGTATTTGTCAAATTTTGCATGAGAAGATCACAATTTTA
		GTGACTCATCAGTTGCAGTACCTCAAAGCTGCAAGTCAGATTCTGATATTGAAAGATGGTAAAATGGT
		GCAGAAGGGGACTTACACTGAGTTCCTAAAATCTGGTATAGATTTTGGCTCCCTTTTAAAGAAGGATA
		ATGAGGAAAGTGAACAACCTCCAGTTCCAGGAACTCCCACACTAAGGAATCGTACCTTCTCAGAGTCT
		TCGGTTTGGTCTCAACAATCTTCTAGACCCTCCTTGAAAGATGGTGCTCTGGAGAGCCAAGATACAGA
		GAATGTCCCAGTTACACTATCAGAGGAGAACCGTTCTGAAGGAAAAGTTGGTTTTCAGGCCTATAAGA
		ATTACTTCAGAGCTGGTGCTCACTGGATTGTCTTCATTTTCCTTATTCTCCTAAACACTGCAGCTC
		AGGTTGCCTATGTGCTTCAAGATTGGTGGCTTTCATACTGGGCAAACAAACAAAGTATGCTAAATGTC
		ACTGTAAATGGAGGAGGAAATGTAACCGAGAAGCTAGATCTTAACTGGTACTTAGGAATTTATTCAGG
		TTTAACTGTAGCTACCGTTCTTTTTGGCATAGCAAGATCTCTATTGGTATTCTACGTCCTTGTTAACT
		CTTCACAAACTTTGCACAACAAAATGTTTGAGTCAATTCTGAAAGCTCCGGTATTATTCTTTGATAGA
		AATCCAATAGGAAGAATTTTAAATCGTTTCTCCAAAGACATTGGACACTTGGATGATTTGCTGCCGCT
		GACGTTTTTAGATTTCATCCAGAGATGGGATCTCGCTGTGTTGTCCTGGCTGGTCTCAAACTCCTAGG
		CTCAAGCAATCCTCCTCCCTCCTCAAGCAAACCTCAGTGCTGGGATTATAGGCATGAGCCACTGTACC
		TGGCTAAATGTTGTTTTTTTGATATTCAATTTTTGTTTATAGAATTTTCATTTGTTTTGCTCTTATAC
		TTTTCATCTTTTTATGTTTATTGACCAATTAAATATCATTTGGGTAAGCACCTATTTAAGTGTCTTAA
		CAATTTTTCTATTGAGTACTCTGGGTTTTTGTTTTGTTTTTCTTACTGATTTGTAGAATTCTTTATGT
		ATTCTGAATTGCAGATACCTTCCTTCTGTACTAATGCTTATCTTTTTAGCCCTGTAATATTGTGTTTT
		CATAAACATACTTATCAATCTTT

7185	Human ABCC4	GCTTCACAGGCTCCAGCCGAGCGGACAGGCGTGGCGGCCGGAGCCCCAGCATCCCTGCTTGAGGTCCA
	transcript	GGAGCGGAGCCCGCGGCCACCGCCGCCTGATCAGCGCGACCCCGGCCCGCGCCCGCCCCGCCCGGCAA
	variant	GATGCTGCCCGTGTACCAGGAGGTGAAGCCCAACCCGCTGCAGGACGCGAACCTCTGCTCACGCGTGT
	3 mRNA	TCTTCTGGTGGCTCAATCCCTTGTTTAAAATTGGCCATAAACGGAGATTAGAGGAAGATGATATGTAT
	NM_001301829.	TCAGTGCTGCCAGAAGACCGCTCACAGCACCTTGGAGAGGAGTTGCAAGGGTTCTGGGATAAAGAAGT
	2	TTTAAGAGCTGAGAATGACGCACAGAAGCCTTCTTTAACAAGAGCAATCATAAAGTGTTACTGGAAAT
	(GI:1677530022	CTTATTTAGTTTTGGGAATTTTTACGTTAATTGAGGAAAGTGCCAAAGTAATCCAGCCCATATTTTTG
	version 2)	GGAAAAATTATTAATTATTTTGAAAATTATGATCCCATGGATTCTGTGGCTTTGAACACAGCGTACGC
		CTATGCCACGGTGCTGACTTTTTGCACGCTCATTTTGGCTATACTGCATCACTTATATTTTTATCACG
		TTCAGTGTGCTGGGATGAGGTTACGAGTAGCCATGTGCCATATGATTTATCGGAAGGCACTTCGTCTT
		AGTAACATGGCCATGGGGAAGACAACCACAGGCCAGATAGTCAATCTGCTGTCCAATGATGTGAACAA
		GTTTGATCAGGTGACAGTGTTCTTACACTTCCTGTGGGCAGGACCACTGCAGGCGATTGCAGTGACTG
		CCCTACTCTGGATGGAGATAGGAATATCGTGCCTTGCTGGGATGGCAGTTCTAATCATTCTCCTGCCC
		TTGCAAAGCTGTTTTGGGAAGTTGTTCTCATCACTGAGGAGTAAAACTGCAACTTTCACGGATGCCAG
		GATCAGGACCATGAATGAAGTTATAACTGGTATAAGGATAATAAAAATGTACGCCTGGGAAAAGTCAT
		TTTCAAATCTTATTACCAATTTGAGAAAGAAGGAGATTTCCAAGATTCTGAGAAGTTCCTGCCTCAGA
		GGGATGAATTTGGCTTCATTTTTCAGTGCAAGCAAAATCATCGTGTTTGTGACCTTCACCACCTACGT
		GCTCCTCGGCAGTGTGATCACAGCCAGCCGCGTGTTCGTGGCAGTGACGCTGTATGGGGCTGTGCGGC
		TGACGGTTACCCTCTTCTTCCCCTCAGCCATTGAGAGGGTGTCAGAGGCAATCGTCAGCATCCGAAGA
		ATCCAGACCTTTTTGCTACTTGATGAGATATCACAGCGCAACCGTCAGCTGCCGTCAGATGGTAAAAA
		GATGGTGCATGTGCAGGATTTTACTGCTTTTTGGGATAAGGCATCAGAGACCCCAACTCTACAAGGCC
		TTTCCTTTACTGTCAGACCTGGCGAATTGTTAGCTGTGGTCGGCCCCGTGGGAGCAGGGAAGTCATCA
		CTGTTAAGTGCCGTGCTCGGGGAATTGGCCCCAAGTCACGGGCTGGTCAGCGTGCATGGAAGAATTGC
		CTATGTGTCTCAGCAGCCCTGGGTGTTCTCGGGAACTCTGAGGAGTAATATTTTATTTGGGAAGAAAT
		ACGAAAAGGAACGATATGAAAAAGTCATAAAGGCTTGTGCTCTGAAAAAGGATTTACAGCTGTTGGAG
		GATGGTGATCTGACTGTGATAGGAGATCGGGGAACCACGCTGAGTGGAGGGCAGAAAGCACGGGTAAA
		CCTTGCAAGAGCAGTGTATCAAGATGCTGACATCTATCTCCTGGACGATCCTCTCAGTGCAGTAGATG
		CGGAAGTTAGCAGACACTTGTTCGAACTGTGTATTTGTCAAATTTTGCATGAGAAGATCACAATTTTA
		GTGACTCATCAGTTGCAGTACCTCAAAGCTGCAAGTCAGATTCTGATATTGAAAGATGGTAAAATGGT
		GCAGAAGGGGACTTACACTGAGTTCCTAAAATCTGGTATAGATTTTGGCTCCCTTTTAAAGAAGGATA
		ATGAGGAAAGTGAACAACCTCCAGTTCCAGGAACTCCCACACTAAGGAATCGTACCTTCTCAGAGTCT
		TCGGTTTGGTCTCAACAATCTTCTAGACCCTCCTTGAAAGATGGTGCTCTGGAGAGCCAAGATGTTGC
		CTATGTGCTTCAAGATTGGTGGCTTTCATACTGGGCAAACAAACAAAGTATGCTAAATGTCACTGTAA
		ATGGAGGAGGAAATGTAACCGAGAAGCTAGATCTTAACTGGTACTTAGGAATTTATTCAGGTTTAACT
		GTAGCTACCGTTCTTTTTGGCATAGCAAGATCTCTATTGGTATTCTACGTCCTTGTTAACTCTTCACA
		AACTTTGCACAACAAAATGTTTGAGTCAATTCTGAAAGCTCCGGTATTATTCTTTGATAGAAATCCAA
		TAGGAAGAATTTTAAATCGTTTCTCCAAAGACATTGGACACTTGGATGATTTGCTGCCGCTGACGTTT
		TTAGATTTCATCCAGACATTGCTACAAGTGGTTGGTGTGGTCTCTGTGGCTGTGGCCGTGATTCCTTG
		GATCGCAATACCCTTGGTTCCCCTTGGAATCATTTTCATTTTTCTTCGGCGATATTTTTTGGAAACGT
		CAAGAGATGTGAAGCGCCTGGAATCTACAACTCGGAGTCCAGTGTTTTCCCACTTATCATCTTCTCTC
		CAGGGGCTCTGGACCATCCGGGCATACAAAGCAGAAGAGAGGTGTCAGGAACTGTTTGATGCACACCA
		GGATTTACATTCAGAGGCTTGGTTCTTGTTTTTGACAACGTCCCGCTGGTTTGCCGTCCGTCTGGATG
		CCATCTGTGCCATGTTTGTCATCATCGTTGCCTTTGGGTCCCTGATTCTGGCAAAAACTCTGGATGCC
		GGGCAGGTTGGTTTGGCACTGTCCTATGCCCTCACGCTCATGGGGATGTTTCAGTGGTGTGTTCGACA
		AAGTGCTGAAGTTGAGAATATGATGATCTCAGTAGAAAGGGTCATTGAATACACAGACCTTGAAAAAG
		AAGCACCTTGGGAATATCAGAAACGCCCACCACCAGCCTGGCCCCATGAAGGAGTGATAATCTTTGAC
		AATGTGAACTTCATGTACAGTCCAGGTGGGCCTCTGGTACTGAAGCATCTGACAGCACTCATTAAATC
		ACAAGAAAAGGTTGGCATTGTGGGAAGAACCGGAGCTGGAAAAAGTTCCCTCATCTCAGCCCTTTTTA
		GATTGTCAGAACCCGAAGGTAAAATTTGGATTGATAAGATCTTGACAACTGAAATTGGACTTCACGAT
		TTAAGGAAGAAGATGTCAATCATACCTCAGGAACCTGTTTTGTTCACTGGAACAATGAGGAAAAACCT
		GGATCCCTTTAATGAGCACACGGATGAGGAACTGTGGAATGCCTTACAAGAGGTACAACTTAAAGAAA
		CCATTGAAGATCTTCCTGGTAAAATGGATACTGAATTAGCAGAATCAGGATCCAATTTTAGTGTTGGA
		CAAAGACAACTGGTGTGCCTTGCCAGGGCAATTCTCAGGAAAAATCAGATATTGATTATTGATGAAGC
		GACGGCAAATGTGGATCCAAGAACTGATGAGTTAATACAAAAAAAAATCCGGGAGAAATTTGCCCACT
		GCACCGTGCTAACCATTGCACACAGATTGAACACCATTATTGACAGCGACAAGATAATGGTTTTAGAT
		TCAGGAAGACTGAAAGAATATGATGAGCCGTATGTTTTGCTGCAAAATAAAGAGAGCCTATTTTACAA
		GATGGTGCAACAACTGGGCAAGGCAGAAGCCGCTGCCCTCACTGAAACAGCAAAACAGGTATACTTCA
		AAAGAAATTATCCACATATTGGTCACACTGACCACATGGTTACAAACACTTCCAATGGACAGCCCTCG
		ACCTTAACTATTTTCGAGACAGCACTGTGAATCCAACCAAAATGTCAAGTCCGTTCCGAAGGCATTTT
		CCACTAGTTTTTGGACTATGTAAACCACATTGTACTTTTTTTTACTTTGGCAACAAATATTTATACAT
		ACAAGATGCTAGTTCATTTGAATATTTCTCCCAACTTATCCAAGGATCTCCAGCTCTAACAAAATGGT
		TTATTTTTATTTAAATGTCAATAGTTGTTTTTTAAAATCCAAATCAGAGGTGCAGGCCACCAGTTAAA
		TGCCGTCTATCAGGTTTTGTGCCTTAAGAGACTACAGAGTCAAAGCTCATTTTTAAAGGAGTAGGACA
		AAGTTGTCACAGGTTTTTGTTGTTGTTTTTATTGCCCCCAAAATTACATGTTAATTTCCATTTATATC
		AGGGATTCTATTTACTTGAAGACTGTGAAGTTGCCATTTTGTCTCATTGTTTTCTTTGACATAACTAG
		GATCCATTATTTCCCCTGAAGGCTTCTTGTTAGAAAATAGTACAGTTACAACCAATAGGAACAACAAA
		AAGAAAAAGTTTGTGACATTGTAGTAGGGAGTGTGTACCCCTTACTCCCCATCAAAAAAAAAAATGGA
		TACATGGTTAAAGGATAGAAGGGCAATATTTTATCATATGTTCTAAAAGAGAAGGAAGAGAAAATACT
		ACTTTCTCAAAATGGAAGCCCTTAAAGGTGCTTTGATACTGAAGGACACAAATGTGACCGTCCATCCT
		CCTTTAGAGTTGCATGACTTGGACACGGTAACTGTTGCAGTTTTAGACTCAGCATTGTGACACTTCCC
		AAGAAGGCCAAACCTCTAACCGACATTCCTGAAATACGTGGCATTATTCTTTTTTGGATTTCTCATTT
		ATGGAAGGCTAACCCTCTGTTGACTGTAAGCCTTTTGGTTTGGGCTGTATTGAAATCCTTTCTAAATT
		GCATGAATAGGCTCTGCTAACGTGATGAGACAAACTGAAAATTATTGCAAGCATTGACTATAATTATG
		CAGTACGTTCTCAGGATGCATCCAGGGGTTCATTTTCATGAGCCTGTCCAGGTTAGTTTACTCCTGAC
		CACTAATAGCATTGTCATTTGGGCTTTCTGTTGAATGAATCAACAAACCACAATACTTCCTGGGACCT
		TTTGTACTTTATTTGAACTATGAGTCTTTAATTTTTCCTGATGATGGTGGCTGTAATATGTTGAGTTC
		AGTTTACTAAAGGTTTTACTATTATGGTTTGAAGTGGAGTCTCATGACCTCTCAGAATAAGGTGTCAC
		CTCCCTGAAATTGCATATATGTATATAGACATGCACACGTGTGCATTTGTTTGTATACATATATTTGT
		CCTTCGTATAGCAAGTTTTTTGCTCATCAGCAGAGAGCAACAGATGTTTTATTGAGTGAAGCCTTAAA
		AAGCACACACCACACACAGCTAACTGCCAAAATACATTGACCGTAGTAGCTGTTCAACTCCTAGTACT
		TAGAAATACACGTATGGTTAATGTTCAGTCCAACAAACCACACACAGTAAATGTTTATTAATAGTCAT
		GGTTCGTATTTTAGGTGACTGAAATTGCATCAGTGATCATAATGAGGTTTGTTAAAACGATAGCTATA
		TTCAAAATGTCTATATGTTTATTTGGACTTTTGAGGTTAAAGACAGTCATATAAACGTCCTGTTTCTG
		TTTTAATGTTATCATAGAATTTTTTAATGAAACTAAATTCAATTGAAATAAATGATAGTTTTCATCTC
		CA

7186	Human ABCC4	GCTTCACAGGCTCCAGCCGAGCGGACAGGCGTGGCGGCCGGAGCCCCAGCATCCCTGCTTGAGGTCCA
	transcript	GGAGCGGAGCCCGCGGCCACCGCCGCCTGATCAGCGCGACCCCGGCCCGCGCCCGCCCCGCCCGGCAA
	variant	GATGCTGCCCGTGTACCAGGAGGTGAAGCCCAACCCGCTGCAGGACGCGAACCTCTGCTCACGCGTGT
	4 mRNA	TCTTCTGGTGGCTCAATCCCTTGTTTAAAATTGGCCATAAACGGAGATTAGAGGAAGATGATATGTAT
	NM_001301830.	TCAGTGCTGCCAGAAGACCGCTCACAGCACCTTGGAGAGGAGTTGCAAGGGTTCTGGGATAAAGAAGT
	2	TTTAAGAGCTGAGAATGACGCACAGAAGCCTTCTTTAACAAGAGCAATCATAAAGTGTTACTGGAAAT
	(GI:1677498275	CTTATTTAGTTTTGGGAATTTTTACGTTAATTGAGGCACTTCGTCTTAGTAACATGGCCATGGGGAAG
	version 2)	ACAACCACAGGCCAGATAGTCAATCTGCTGTCCAATGATGTGAACAAGTTTGATCAGGTGACAGTGTT
		CTTACACTTCCTGTGGGCAGGACCACTGCAGGCGATTGCAGTGACTGCCCTACTCTGGATGGAGATAG
		GAATATCGTGCCTTGCTGGGATGGCAGTTCTAATCATTCTCCTGCCCTTGCAAAGCTGTTTTGGGAAG
		TTGTTCTCATCACTGAGGAGTAAAACTGCAACTTTCACGGATGCCAGGATCAGGACCATGAATGAAGT
		TATAACTGGTATAAGGATAATAAAAATGTACGCCTGGGAAAAGTCATTTTCAAATCTTATTACCAATT
		TGAGAAAGAAGGAGATTTCCAAGATTCTGAGAAGTTCCTGCCTCAGAGGGATGAATTTGGCTTCATTT
		TTCAGTGCAAGCAAAATCATCGTGTTTGTGACCTTCACCACCTACGTGCTCCTCGGCAGTGTGATCAC
		AGCCAGCCGCGTGTTCGTGGCAGTGACGCTGTATGGGGCTGTGCGGCTGACGGTTACCCTCTTCTTCC
		CCTCAGCCATTGAGAGGGTGTCAGAGGCAATCGTCAGCATCCGAAGAATCCAGACCTTTTTGCTACTT
		GATGAGATATCACAGCGCAACCGTCAGCTGCCGTCAGATGGTAAAAAGATGGTGCATGTGCAGGATTT
		TACTGCTTTTTGGGATAAGGCATCAGAGACCCCAACTCTACAAGGCCTTTCCTTTACTGTCAGACCTG
		GCGAATTGTTAGCTGTGGTCGGCCCCGTGGGAGCAGGGAAGTCATCACTGTTAAGTGCCGTGCTCGGG
		GAATTGGCCCCAAGTCACGGGCTGGTCAGCGTGCATGGAAGAATTGCCTATGTGTCTCAGCAGCCCTG
		GGTGTTCTCGGGAACTCTGAGGAGTAATATTTTATTTGGGAAGAAATACGAAAAGGAACGATATGAAA
		AAGTCATAAAGGCTTGTGCTCTGAAAAAGGATTTACAGCTGTTGGAGGATGGTGATCTGACTGTGATA
		GGAGATCGGGGAACCACGCTGAGTGGAGGGCAGAAAGCACGGGTAAACCTTGCAAGAGCAGTGTATCA
		AGATGCTGACATCTATCTCCTGGACGATCCTCTCAGTGCAGTAGATGCGGAAGTTAGCAGACACTTGT
		TCGAACTGTGTATTTGTCAAATTTTGCATGAGAAGATCACAATTTTAGTGACTCATCAGTTGCAGTAC
		CTCAAAGCTGCAAGTCAGATTCTGATATTGAAAGATGGTAAAATGGTGCAGAAGGGGACTTACACTGA
		GTTCCTAAAATCTGGTATAGATTTTGGCTCCCTTTTAAAGAAGGATAATGAGGAAAGTGAACAACCTC
		CAGTTCCAGGAACTCCCACACTAAGGAATCGTACCTTCTCAGAGTCTTCGGTTTGGTCTCAACAATCT
		TCTAGACCCTCCTTGAAAGATGGTGCTCTGGAGAGCCAAGATACAGAGAATGTCCCAGTTACACTATC
		AGAGGAGAACCGTTCTGAAGGAAAAGTTGGTTTTCAGGCCTATAAGAATTACTTCAGAGCTGGTGCTC
		ACTGGATTGTCTTCATTTTCCTTATTCTCCTAAACACTGCAGCTCAGGTTGCCTATGTGCTTCAAGAT
		TGGTGGCTTTCATACTGGGCAAACAAACAAAGTATGCTAAATGTCACTGTAAATGGAGGAGGAAATGT
		AACCGAGAAGCTAGATCTTAACTGGTACTTAGGAATTTATTCAGGTTTAACTGTAGCTACCGTTCTTT
		TTGGCATAGCAAGATCTCTATTGGTATTCTACGTCCTTGTTAACTCTTCACAAACTTTGCACAACAAA
		ATGTTTGAGTCAATTCTGAAAGCTCCGGTATTATTCTTTGATAGAAATCCAATAGGAAGAATTTTAAA
		TCGTTTCTCCAAAGACATTGGACACTTGGATGATTTGCTGCCGCTGACGTTTTTAGATTTCATCCAGA
		GATGGGATCTCGCTGTGTTGTCCTGGCTGGTCTCAAACTCCTAGGCTCAAGCAATCCTCCTCCCTCCT
		CAAGCAAACCTCAGTGCTGGGATTATAGGCATGAGCCACTGTACCTGGCTAAATGTTGTTTTTTTGAT
		ATTCAATTTTTGTTTATAGAATTTTCATTTGTTTTGCTCTTATACTTTTCATCTTTTTATGTTTATTG
		ACCAATTAAATATCATTTGGGTAAGCACCTATTTAAGTGTCTTAACAATTTTTCTATTGAGTACTCTG
		GGTTTTTGTTTTGTTTTTCTTACTGATTTGTAGAATTCTTTATGTATTCTGAATTGCAGATACCTTCC
		TTCTGTACTAATGCTTATCTTTTTAGCCCTGTAATATTGTGTTTTCATAAACATACTTATCAATCTTT

7187	Human PAK3	AGAGCATCCTCAGCAGCTGCCACCGAAGCAGCCTCCTCCTTCTCTCTTCCTCCTCCTCCTACCACGGC
	transcript	CGCCGCCACCACCGCTGCGGCTGTGATCTCCTATCCCCTCTGGTCCTCCTTCCTCCCCCAGTTCCTGC
	variant	TCCTCCTCCCATCCCCTGCTCCTCCTGCCCAGCAGCGAAGGGCAGAACCCTCGGCTGCCGCCCTCCTT
	1 mRNA	CGCTCTGACCAAGAAGAGGCTGGAACAGAATAACATACAGAGGACAGCTTTCTCTTCTGAGGAGTCAG
	NM_	AAGTTCAGTTCGCCCAACATGGAATGACTTGAGGAGCTGTGAAATTAGTTGTAACTGAAAATGTCTGA
	001128166.3	CGGTCTGGATAATGAAGAGAAACCCCCGGCTCCTCCACTGAGGATGAATAGTAACAACCGGGATTCTT
	(GI:1889680926	CAGCACTCAACCACAGCTCCAAACCACTTCCCATGGCCCCTGAAGAGAAGAATAAGAAAGCCAGGCTT
	version 3)	CGCTCTATCTTCCCAGGAGGAGGGGATAAAACCAATAAGAAGAAGGAGAAAGAGCGCCCAGAGATCTC
		TCTTCCTTCAGACTTTGAGCATACGATTCATGTGGGGTTTGATGCAGTCACCGGGGAATTCACTGGAA
		TTCCAGAGCAATGGGCACGATTACTCCAAACTTCCAACATAACAAAATTGGAACAGAAGAAGAACCCA
		CAAGCTGTTCTAGATGTTCTCAAATTCTATGATTCCAAAGAAACAGTCAACAACCAGAAATACATGAG
		CTTTACATCAGGAGATAAAAGTGCACATGGATACATAGCAGCCCATCCTTCGAGTACAAAAACAGCAT
		CTGAGCCTCCATTGGCCCCTCCTGTGTCTGAAGAAGAAGATGAAGAGGAAGAAGAAGAAGAAGATGAA
		AATGAGCCACCACCAGTTATCGCACCAAGACCAGAGCATACAAAATCAATCTATACTCGTTCTGTGGT
		TGAATCCATTGCTTCACCAGCAGTACCAAATAAAGAGGTCACACCACCCTCTGCTGAAAATGCCAATT
		CCAGTACTTTGTACAGGAACACAGATCGGCAAAGAAAAAAATCCAAGATGACAGATGAGGAGATCTTA
		GAGAAGCTAAGAAGCATTGTGAGTGTTGGGGACCCAAAGAAAAAATACACAAGATTTGAAAAAATTGG
		TCAAGGGGCATCAGGTACTGTTTATACAGCACTAGACATTGCAACAGGACAAGAGGTGGCCATAAAGC
		AGATGAACCTTCAACAGCAACCCAAGAAGGAATTAATTATTAATGAAATTCTGGTCATGAGGGAAAAT
		AAGAACCCTAATATTGTTAATTATTTAGATAGCTACTTGGTGGGTGATGAACTATGGGTAGTCATGGA
		ATACTTGGCTGGTGGCTCTCTGACTGATGTGGTCACAGAGACCTGTATGGATGAAGGACAGATAGCAG
		CTGTCTGCAGAGAGTGCCTGCAAGCTTTGGATTTCCTGCACTCAAACCAGGTGATCCATAGAGATATA
		AAGAGTGACAATATTCTTCTCGGGATGGATGGCTCTGTTAAATTGACTGACTTTGGGTTCTGTGCCCA
		GATCACTCCTGAGCAAAGTAAACGAAGCACTATGGTGGGAACCCCATATTGGATGGCACCTGAGGTGG
		TGACTCGAAAAGCTTATGGTCCGAAAGTTGATATCTGGTCTCTTGGAATTATGGCAATTGAAATGGTG
		GAAGGTGAACCCCCTTACCTTAATGAAAATCCACTCAGGGCATTGTATCTGATAGCCACTAATGGAAC
		TCCAGAGCTCCAGAATCCTGAGAGACTGTCAGCTGTATTCCGTGACTTTTTAAATCGCTGTCTTGAGA
		TGGATGTGGATAGGCGAGGATCTGCCAAGGAGCTTTTGCAGCATCCATTTTTAAAATTAGCCAAGCCT
		CTCTCCAGCCTGACTCCTCTGATTATCGCTGCAAAGGAAGCAATTAAGAACAGCAGCCGCTAAGACTG
		CAAGCCTTACACCTCACCATCTCCCTCATGAGTAAGACTGAAATAAAACTCTGCTGCAGGAAAGATGG
		AAGAAAAGACAGTCAAATGGGGTGGGGGTTCTTTACCTTTCAAATGAATAGAAACTTCTTATAAGCCT
		TTTTCCTACTCCCTCAGATTATGTAATTTATTTGTAAGCCTGAATCGCAGCCCAAACAGGGCAGCAAT
		GTTGAAGTGACCATAAAGTGGTCACTTCCACCGTGAAGCGAAAGAGCCAGTAGTGAATCCCCTCATTT
		TGTGCATTCACTTTGAAGAAAAAGGTTTCTCAAAGATGCACACTCCCTCTTCATAGTGTTGTGTTTGT
		TTTTAAGTTAGAGAGTAGTCCCTCTTGCATTCAAACCTCCTTCAAAACTCCTTACCCAATGTGATGTT
		TTTCACTTGCATTGTCATTAGATGTCCAGAAAAAAAAAAGATGTCAAAATGTTTTTCTAAAAAAAGAA
		AGCAAAAAAAGCAAGGCAAAAAAAAAAAAAAAAACAAACAAAAACAAAAACAAAACAAAAACAAGCAA
		ACAAAAAATACCAGAGCAAGTACTGTGTGAACATGTGGAAGTCCATGCCCTAATAGAGTTGCAATTTT
		TTATTCTTCTTCTATAGTGGTGGCTTGGTTTGTGTACCTATTTTTCTGCATTTGTATTGGAAAAGGTT
		TCTTTTAAGACATTTTCCAAAAGTGGAGAGGAATATGTGTGTTCAGGAAGGGCTTTCAAAAAACTGTA
		TATCTAAATAAAGCTCAAACGGTGAAATCCTGTCACATTTTCACAATGATGCTTAAAAGATAATTGAG
		TAAACCAGGTTGTTAATCTCCTTAATACCTGAAAGAGGACACACTGAAACTGAAACTGTGACATCCTG
		CTAGGTGAGTTCAGGTTCTGAACCTAGGAAATCCTCATAGGAGAAACCACATTTAAACAAAGATGGGA
		CTTTCTCTGAGAGCCAAAACCAGATAAATGTAGAATACTGAAATCCTTGTTGGACATTAAGTAAACAA
		AGATAATGATACCTAAATTAATCCTCTCTTGTGCTTATGAAACATATGCACTGTAAAATAGGCATACC
		AGGAGGAAATAGATACATTAATCATCATTTACTTATGATACAAATTATTTATTTTGACAATTTATAAC
		GTTTAAAAAAGTTTTTTAAAGATCTAGAGAAAGGTGATATAGTAAACATTCAACTCTGTAAGAAATGG
		GAGGTCAGTGAAGGCTACATCCCAATCAATATTTGGCTCTAAGTACCTCTTCCCATTTTTCCTATGTA
		TCACCTATTTCTGTTTCGGAATATGGTGTGTTCATGCTTAGTTCTTTGGGCTTTTGAATATCAAAAGC
		ATATTCATAAATGTCTTGAAATTCTCTCCAGTGGAAAATAATTTTAACTTACAATCATATCCCAAGAA
		ATGTCAGTCCGACAGAATTCCTTATATGACTTGGGGAAAATAACAAAATTTGACTACTATTTCACCAT
		ATATCTATTTATTAAAAAATTCAACAGTTGGCACTTCCTGAATCTTCTGAGAGTAGAAAAATATCTGC
		GGAGTGTCTGTGTAGAAAAGGATATGCCTCTCTTTTGAGTGTATTGACAATTTTGTAAATTACAGAAA
		GTTGTTTCTCTAAGCCTTTGAAAAACTAACAATTTGTGTTATAGAAGGCTTCTTAATTTGCAGTATAA
		AAGAATCTAAACAGAACTTATGTACATTCAGCCAGAAGGGGAAAGAGATCAGTTACATAGGCCTCTCT
		CCTTCTTTGCCAAGGTACATCCATCCATCTAACCATCCATATATCCACATCTTAAAATGAAAGCACTT
		TCTTTAGAGTTTCAGCAAACTATATAGTGTACGTGTTTATGTTCAGGAGATGACCCCACTGGTGTATT
		TCCTATTTTCCCTATTGTTTTCTTTGACTGTAAAAGTTGGGAGAGGCTTGACCTCCTCCCCTTGAAAA
		TGTCCACAGTGGGATAAAACAACAAATGTGAAAAGAAAATGAAACGGTAATATTAATTTGAAGCATAC
		TATGTTATACTTTGCAAAAACGAATCTGGGCCTGTAATTTTTAATGCCACACTGCTCTAATGAGAGAG
		AGAGGCCTTAATTTTGATTTCATTTAAAAATAAGTACTTTAAAAAATTTTTCACTCATAGTGCCGGGA
		AATTCAATGAAATCCTGGGATGCAAATAAAAATCAGTACATTAGTGACTGTGTCCTGCCAGTGGAGAG
		AGCCCAATACCTGGTTAGGAAGCCCTATTCATTAGTTAGCATCCCTTACATGTTGAGAAGGCCTTTTT
		TTTGTTGTTATTTTGGAGACCTTGGAGCAGTGACCCTTCAGATCACTGTAGGCAGAGAAATGGCTTCT
		CTCTTATGCTTTCAGTTCAGCATATTAACAATGAGGAGCCAGGTACTTCTTTACTACCACTTTGTACC
		AAGATTTGATAATAATATATCCCAGGAGGCATTACTTTTATAAATTTGTATTCATGTAAATTTTCAAA
		TGAGAACAGCTTCTAAAGCCCCTTCCCTGTATTGGAGAGTTATGTATATTTCTAATAAGTATTAGAAA
		GAAGCTGTTTCTCATGCCACAGTGATGCTGAAGGATTCACATTTGGTACAATCGAGTAACTTGAACGC
		CAGATTGTTAACAGTTTATTCTCTTTCCCTGGATTTTTAAGCTCATCTTGACACAGGTGAGTCTATCC
		AAATCTTTGATGTTGCTAGTGTGCCCTGAGATAACGAGGGCACATCTTTCAATGTTGATTCCAAAATG
		TCCTGAGTTAGGAATAGGGCAGTGGGAAAGTCAGGGAAGGGTGAGAAGCACAGTAGAGATTATTTATT
		TAAAAAAGGAAAGAACGTTAATGTTGTTAGCAAGGATCCAGTGCGTTGTCATAATCCCATGAGGATTT
		TCAGATGACACAATCCCCTCAAATCAGTCACCATGTTGGGTAATGACTTCGTTCTTGCTGATCTCGTG
		TGTGTGTCATTGTAAATATTTGTGTGTCCATGTTCCATTTTGGCTACTGGATGGCCAAGCCATGTAAG
		AAGATTTAACTCAAGTATTTATTCTTTATGTTATTCAGATTTCTTTCAGGCTTGTGAACTGCACCCCA
		ATGTTTGAGTTTAACCACCTGATCCTTACATCTATCCCTCCCCGGTGAAGCACATTCCATTGCTAAAA
		GAAAAAGAAACACGAAATTGCTTCCTGTTGTCTGTATAACTGTTTTGATAGTTTGAGATATTTGTCTA
		TAAATGATATTTCTCAGCTCAAAGATCGTGTAAATAATTATATTCCTTTGCTCAATGGGTTTATTTCT
		AATGAGGCTGCCAGTTCTGAGAGATTCTATAATATCACTTTTAAATAACATAAACAGGGATTACAACT
		ATGTAAAAAGAAATGCATATGGACAAAGACTGGGAACACAGATAATTGAAATCAGTTGTGTTAGGGTG
		GTGGAATTATGTGAATTTTTTTTTCTTTTTAAAATTTTATTTGATATTGTTATAATATTGCTTTACAA
		TAAATAAACAGCAGAAAGGGAACTATAGACACATAGAAAAGATGCCAGAAGCAGATGCCTTCTGGCCA
		GAGCGCAGAGCATGCAGGGCAGAGATATTTGCTAGTTACAATTATTCCATAGGCTTTATGCTTGCCTG
		GGTGCTGAGGTTGGCACACGCTCGGGTATGGCACACGCTTTCTTAGGAGACTATTATCTATAAGTTAA
		AGCTAGGGAGATGTCACTATTAGAACTCCAAACACACTCTTCTGCTTTAAAACAGGTTGTCTGCCCTC
		TGCTTTGGTATGGCATTCGGGTGTCTGTTTTGTGGTTGCTTTAGATTGGAGGGGTGACCATTTTATTA
		GCCCCCTTGATAACATCTGTTGCAGATATTGCCTTTCTGGAACGTTTTAACAGACTCTCAGGTTGAAT
		TTTGGAGGACTAGAAGGATAAAATCCCCAGCTCCCACCATTTTCTTGTCCAACAGGATATTACTGTAT
		ATCATTCAGGTAGGATTCTTCTTTTAATAACCAATAGGGCAAGTCCCACTAATTTCAATAGAAGTTAT
		GACTTGCAATTAAAAGCTGACTTTGAAATCATTAAACAAATATGTAGGACTGTCTCTGCCTGTTGGCA
		TTCAGTTATAGTTCTGTTAATTTTGGCTTGGGATGGTCTCCATGTGCTTTTTTCTGCCTATTTATAGG
		TTGTTTGCAGTAGTTGTGATTTTTAAAGAGCAAGGGAGACCATCTAACCAAAGGATAACTTCCTTCTA
		ACTCACCAAAGAAATTTTAGGTGAGAACTTTAATAATGAGGTAGTCACCTCAGATATGCTGCTTAGTT
		TCACTAAAAGCAGACCCTATACCTAGAGAAGTCACTGGCTTTTTATTGGTCATTCTCAATACAGAAAT
		ACTTAGGGGAGTCTTAACCCTGCCATCCCCGGTTGAATCTCTTGGTCTTTATCTAAGCTACTTGCAGT
		TAATATTCAGTTAAGCAAAGGTATGGCCAGTAGTGCAAGTATCTCCCAGTCTCTGAGCTCTGAACAAG
		AGGACTGAAATTCAGCATTTGTAAACTGACAGTTTGATGGGCCTGGGATTTGAAGTGAACTCAGCACA
		CAATTCTGAACGTGTATTTGCATGTGGACTGGGAAGGAAATAAATGGGAACTTGGAAATAATGGAATA
		TTTCTCCTATGAAAGAATTTTTCGTAGAAGATTTGTTTTTGATATAATCTTTCTGTTGGTTAGCTTTT
		AGTGTTTTCATTCCTTTTCTGATCCACACTCCTTTAAGTGACCAAATGAATATAACCCAACATGCATT
		GGGAATGTGTTTAATATTAAACAATGTCTAACTGAATCTGCAAATGCGGGAACTGAGATATCACCTCC
		ATGTGCACACCTGTGTGTACGAGTATTCTATACAACTTGTAGCATTTACTGCCACTTAATTG
		GGTTGAACTTGCAAGATAAACTTTTGGAAACTGCTTAGTGCCATCGGAGTCTCCTTTAGAAGCTGCCA
		TCAGGCAAATGCTATCCCATAATACCAGCAGTAAGCCTGGCAACATGTTCAACAGATTTAGTACCCAA
		GAGGAAATCAACAGCGATAGTAGAGAATGAGTCAGATGTAGTGGGATAAATACTAGCCTAGGAAGAAG
		GAGCCCCGGAGTCTAATATGAGCTTTATTACTAAATTGCTATGTGACGCTAGGCAAGTCACTTAACCT
		CTCCATGGCTGTTTCCTCATCTGTAAAATAAGTGTATTGGACTAGATGATCCTTAGGGTCTTTCCAAA
		AGTCTAACATTCTATGGCATTATAGGTTGCCTTGCAAATTCAGCCTGCTATAGTGATGGCAAATATCA
		CGTTTAAGCCTGAGTCTCTTATGTTGCAGTTAAATAAAAGAACTATGTAAGATGATTTTTAAAATTCA
		AGCAAATGGGCCGGGTGCGGTGGCTCATACCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGCGGA
		TCACCTGAGGTCAGGAGTTCGAGACCAGCCTGACCAACATAGAGAAACCCCATCTCTACTAAAAATAC
		AAAATTAGCCGGGTGTGGTGGCGGGCGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGTGGGAGAATC
		GCTTGAACCCAGGAGGCGGAGGTTGTGGTGAGCTGAGATCATGCCATTGCACTCCAGCCTCGGCAACA
		AGAGTGAAACTTCGTCTCCAAAAAAAAAAACTCAAGCAAATGAAGTTCATAATAATAGGGGATGTTGA
		TAAAACTTGTGGCAGCCTTCCAATTCATTTACAGTTGTTTCGTTTTGTTTTTGTTTTAATGTCCATTT
		TCTGTTGACTGTTCCCAGTTTTCATTTTCCATACAGTCTGTATGTAAAGTCTGGTTTTCATTAAGCTG
		TGGCCAGTATTTGCCACTACAACAGAAACACACTGTCACACTTGCTAGAATATAACTGTACTTGAGCT
		TCTCCTTTCCTGTGAAGTAGTGCTGGGCTTTCTAGAGTTTAATTCTCAAGTGGCACAAGATAGCAGAG
		CCCATGCATTTTAATGGCTGAGACTGCTAAGAGTGAACCTAAACACTTACAAGTTGCAGAGAGAAATG
		AAAAAGTAATTACATGCTATTAGCATTGAGAAATGTTGACAAATTAATTTGTTGGGAACCAAAGATAG
		CATTTCTGATGACAACTCCCACAGTGATTGGCCAGTTGTATGATGAGTACACTGCTGGAAAGAGGGTA
		AACTGGGAGTTAGTGGATGGTCCCAATGCCCTGCCTACAGCAGAGTGCCAACCAGCCCTGAGTGCAAA
		ATTCAAGTTCAATGTGTGTGCTTGTGTGTGGTGTGCTTTATGGACCCGCAAATACCATATTCATTATT
		GATGATAAGATCTTCACAGAATCCTGTAGCTACTAATGCATTGAGTTTTTAATCTCAGTACATCAGCC
		AGGAGGAGCCAGATCACAGGGTAGTGATGTCTACTGGGATTATACTCATAACATCTACACAAAACAAG
		TTGAGAAGGATCCACGTTTTCATTGTTTATCAGAATTGTATCTCATTTGGCTGAGCATTACTTTTGTC
		AGAATGTGTTATCTGTAAACCATGTGTAGTGAAATTCTTCTGTAACTTTGGATTAAAGGTATTTATGG
		TCTTTTTGTTTGTTTGATTTTTAAGTAAGTTATTTCTTTTGTAGACCTGCTGATGGTATGGTTCCATC
		CTTCTGACCTCAGCATCCAATCTTTTTAAGGATTTTTGTTTTCAATATTGTTATTTTAAATTGTGGTT
		GAAGCAATAGAAAATTGAAATATGGATTGTGCATGACTGTGTCTTGAGTGTAAAAATATTGCAGTTTG
		AAACTTGGACCTAAAGTATTGCAAATAAAAATGACAAACATCAATGA

7188	Human PAK3	ACCGCGGGCGGGCAGCTGTGCCAGCTAACCGTCTGGGATCTCGCACTGGGGGCTGCAGCTTTTCCCCG
	transcript	CCTCGAGCCAGTGTGCGGGGGCGGGAGAAGAGCCAGGGGGAGCGGGCTGGGCCCGGGGCTGCGGCTGC
	variant	GGCCGCGGGGCTGCGGCTCCCCAGCCCCGCCAGCTGGAGCGCTCGGAGGTAGAGGAAAGGTCTTGACG
	2 mRNA	GGGTGGCTGGATCCGTGGCAGAATCCAGTTCCAGATTCTAGACTTGAGGGTTCTGGGCTGTTGGTCTG
	NM_002578.5	TAGAAGCGAAGGAGAGAAGGACTCAAATCCAGGCCAAGTGTATGGCTGTCTGAGGTATTGGAACAGAA
	(GI:1519316149	GGAGGTCCATTCCTGTTGGTGACAACACCGTGGCCCTGTTCTGGGATGAGCAAGGTGTAAAGGTTTCC
	version 5)	CCCAAGAAAGAGCAGCTGAGTCCTTGCATCTTGTGGCAGCTGGTGTGCCCAGCACTGAGTCTGTAGGA
		GCTGAAGCCAGCCCGGACCCTTCTCATGGGCAGTGCCCACCTGTGCTGAAGTCCTGCAGCGGTGGCGG
		TGTGAGGAGCTGTGAAATTAGTTGTAACTGAAAATGTCTGACGGTCTGGATAATGAAGAGAAACCCCC
		GGCTCCTCCACTGAGGATGAATAGTAACAACCGGGATTCTTCAGCACTCAACCACAGCTCCAAACCAC
		TTCCCATGGCCCCTGAAGAGAAGAATAAGAAAGCCAGGCTTCGCTCTATCTTCCCAGGAGGAGGGGAT
		AAAACCAATAAGAAGAAGGAGAAAGAGCGCCCAGAGATCTCTCTTCCTTCAGACTTTGAGCATACGAT
		TCATGTGGGGTTTGATGCAGTCACCGGGGAATTCACTGGAATTCCAGAGCAATGGGCACGATTACTCC
		AAACTTCCAACATAACAAAATTGGAACAGAAGAAGAACCCACAAGCTGTTCTAGATGTTCTCAAATTC
		TATGATTCCAAAGAAACAGTCAACAACCAGAAATACATGAGCTTTACATCAGGAGATAAAAGTGCACA
		TGGATACATAGCAGCCCATCCTTCGAGTACAAAAACAGCATCTGAGCCTCCATTGGCCCCTCCTGTGT
		CTGAAGAAGAAGATGAAGAGGAAGAAGAAGAAGAAGATGAAAATGAGCCACCACCAGTTATCGCACCA
		AGACCAGAGCATACAAAATCAATCTATACTCGTTCTGTGGTTGAATCCATTGCTTCACCAGCAGTACC
		AAATAAAGAGGTCACACCACCCTCTGCTGAAAATGCCAATTCCAGTACTTTGTACAGGAACACAGATC
		GGCAAAGAAAAAAATCCAAGATGACAGATGAGGAGATCTTAGAGAAGCTAAGAAGCATTGTGAGTGTT
		GGGGACCCAAAGAAAAAATACACAAGATTTGAAAAAATTGGTCAAGGGGCATCAGGTACTGTTTATAC
		AGCACTAGACATTGCAACAGGACAAGAGGTGGCCATAAAGCAGATGAACCTTCAACAGCAACCCAAGA
		AGGAATTAATTATTAATGAAATTCTGGTCATGAGGGAAAATAAGAACCCTAATATTGTTAATTATTTA
		GATAGCTACTTGGTGGGTGATGAACTATGGGTAGTCATGGAATACTTGGCTGGTGGCTCTCTGACTGA
		TGTGGTCACAGAGACCTGTATGGATGAAGGACAGATAGCAGCTGTCTGCAGAGAGTGCCTGCAAGCTT
		TGGATTTCCTGCACTCAAACCAGGTGATCCATAGAGATATAAAGAGTGACAATATTCTTCTCGGGATG
		GATGGCTCTGTTAAATTGACTGACTTTGGGTTCTGTGCCCAGATCACTCCTGAGCAAAGTAAACGAAG
		CACTATGGTGGGAACCCCATATTGGATGGCACCTGAGGTGGTGACTCGAAAAGCTTATGGTCCGAAAG
		TTGATATCTGGTCTCTTGGAATTATGGCAATTGAAATGGTGGAAGGTGAACCCCCTTACCTTAATGAA
		AATCCACTCAGGGCATTGTATCTGATAGCCACTAATGGAACTCCAGAGCTCCAGAATCCTGAGAGACT
		GTCAGCTGTATTCCGTGACTTTTTAAATCGCTGTCTTGAGATGGATGTGGATAGGCGAGGATCTGCCA
		AGGAGCTTTTGCAGCATCCATTTTTAAAATTAGCCAAGCCTCTCTCCAGCCTGACTCCTCTGATTATC
		GCTGCAAAGGAAGCAATTAAGAACAGCAGCCGCTAAGACTGCAAGCCTTACACCTCACCATCTCCCTC
		ATGAGTAAGACTGAAATAAAACTCTGCTGCAGGAAAGATGGAAGAAAAGACAGTCAAATGGGGTGG
		GGGTTCTTTACCTTTCAAATGAATAGAAACTTCTTATAAGCCTTTTTCCTACTCCCTCAGATTATGTA
		ATTTATTTGTAAGCCTGAATCGCAGCCCAAACAGGGCAGCAATGTTGAAGTGACCATAAAGTGGTCAC
		TTCCACCGTGAAGCGAAAGAGCCAGTAGTGAATCCCCTCATTTTGTGCATTCACTTTGAAGAAAAAGG
		TTTCTCAAAGATGCACACTCCCTCTTCATAGTGTTGTGTTTGTTTTTAAGTTAGAGAGTAGTCCCTCT
		TGCATTCAAACCTCCTTCAAAACTCCTTACCCAATGTGATGTTTTTCACTTGCATTGTCATTAGATGT
		CCAGAAAAAAAAAAGATGTCAAAATGTTTTTCTAAAAAAAGAAAGCAAAAAAAGCAAGGCAAAAAAAA
		AAAAAAAAACAAACAAAAACAAAAACAAAACAAAAACAAGCAAACAAAAAATACCAGAGCAAGTACTG
		TGTGAACATGTGGAAGTCCATGCCCTAATAGAGTTGCAATTTTTTATTCTTCTTCTATAGTGGTGGCT
		TGGTTTGTGTACCTATTTTTCTGCATTTGTATTGGAAAAGGTTTCTTTTAAGACATTTTCCAAAAGTG
		GAGAGGAATATGTGTGTTCAGGAAGGGCTTTCAAAAAACTGTATATCTAAATAAAGCTCAAACGGTGA
		AATCCTGTCACATTTTCACAATGATGCTTAAAAGATAATTGAGTAAACCAGGTTGTTAATCTCCTTAA
		TACCTGAAAGAGGACACACTGAAACTGAAACTGTGACATCCTGCTAGGTGAGTTCAGGTTCTGAACCT
		AGGAAATCCTCATAGGAGAAACCACATTTAAACAAAGATGGGACTTTCTCTGAGAGCCAAAACCAGAT
		AAATGTAGAATACTGAAATCCTTGTTGGACATTAAGTAAACAAAGATAATGATACCTAAATTAATCCT
		CTCTTGTGCTTATGAAACATATGCACTGTAAAATAGGCATACCAGGAGGAAATAGATACATTAATCAT
		CATTTACTTATGATACAAATTATTTATTTTGACAATTTATAACGTTTAAAAAAGTTTTTTAAAGATCT
		AGAGAAAGGTGATATAGTAAACATTCAACTCTGTAAGAAATGGGAGGTCAGTGAAGGCTACATCCCAA
		TCAATATTTGGCTCTAAGTACCTCTTCCCATTTTTCCTATGTATCACCTATTTCTGTTTCGGAATATG
		GTGTGTTCATGCTTAGTTCTTTGGGCTTTTGAATATCAAAAGCATATTCATAAATGTCTTGAAATTCT
		CTCCAGTGGAAAATAATTTTAACTTACAATCATATCCCAAGAAATGTCAGTCCGACAGAATTCCTTAT
		ATGACTTGGGGAAAATAACAAAATTTGACTACTATTTCACCATATATCTATTTATTAAAAAATTCAAC
		AGTTGGCACTTCCTGAATCTTCTGAGAGTAGAAAAATATCTGCGGAGTGTCTGTGTAGAAAAGGATAT
		GCCTCTCTTTTGAGTGTATTGACAATTTTGTAAATTACAGAAAGTTGTTTCTCTAAGCCTTTGAAAAA
		CTAACAATTTGTGTTATAGAAGGCTTCTTAATTTGCAGTATAAAAGAATCTAAACAGAACTTATGTAC
		ATTCAGCCAGAAGGGGAAAGAGATCAGTTACATAGGCCTCTCTCCTTCTTTGCCAAGGTACATCCATC
		CATCTAACCATCCATATATCCACATCTTAAAATGAAAGCACTTTCTTTAGAGTTTCAGCAAACTATAT
		AGTGTACGTGTTTATGTTCAGGAGATGACCCCACTGGTGTATTTCCTATTTTCCCTATTGTTTTCTTT
		GACTGTAAAAGTTGGGAGAGGCTTGACCTCCTCCCCTTGAAAATGTCCACAGTGGGATAAAACAACAA
		ATGTGAAAAGAAAATGAAACGGTAATATTAATTTGAAGCATACTATGTTATACTTTGCAAAAACGAAT
		CTGGGCCTGTAATTTTTAATGCCACACTGCTCTAATGAGAGAGAGAGGCCTTAATTTTGATTTCATTT
		AAAAATAAGTACTTTAAAAAATTTTTCACTCATAGTGCCGGGAAATTCAATGAAATCCTGGGATGCAA
		ATAAAAATCAGTACATTAGTGACTGTGTCCTGCCAGTGGAGAGAGCCCAATACCTGGTTAGGAAGCCC
		TATTCATTAGTTAGCATCCCTTACATGTTGAGAAGGCCTTTTTTTTGTTGTTATTTTGGAGACCTTGG
		AGCAGTGACCCTTCAGATCACTGTAGGCAGAGAAATGGCTTCTCTCTTATGCTTTCAGTTCAGCATAT
		TAACAATGAGGAGCCAGGTACTTCTTTACTACCACTTTGTACCAAGATTTGATAATAATATATCCCAG
		GAGGCATTACTTTTATAAATTTGTATTCATGTAAATTTTCAAATGAGAACAGCTTCTAAAGCCCCTTC
		CCTGTATTGGAGAGTTATGTATATTTCTAATAAGTATTAGAAAGAAGCTGTTTCTCATGCCACAGTGA
		TGCTGAAGGATTCACATTTGGTACAATCGAGTAACTTGAACGCCAGATTGTTAACAGTTTATTCTCTT
		TCCCTGGATTTTTAAGCTCATCTTGACACAGGTGAGTCTATCCAAATCTTTGATGTTGCTAGTGTGCC
		CTGAGATAACGAGGGCACATCTTTCAATGTTGATTCCAAAATGTCCTGAGTTAGGAATAGGGCAGTGG
		GAAAGTCAGGGAAGGGTGAGAAGCACAGTAGAGATTATTTATTTAAAAAAGGAAAGAACGTTAATGTT
		GTTAGCAAGGATCCAGTGCGTTGTCATAATCCCATGAGGATTTTCAGATGACACAATCCCCTCAAATC
		AGTCACCATGTTGGGTAATGACTTCGTTCTTGCTGATCTCGTGTGTGTGTCATTGTAAATATTTGTGT
		GTCCATGTTCCATTTTGGCTACTGGATGGCCAAGCCATGTAAGAAGATTTAACTCAAGTATTTATTCT
		TTATGTTATTCAGATTTCTTTCAGGCTTGTGAACTGCACCCCAATGTTTGAGTTTAACCACCTGATCC
		TTACATCTATCCCTCCCCGGTGAAGCACATTCCATTGCTAAAAGAAAAAGAAACACGAAATTGCTTCC
		TGTTGTCTGTATAACTGTTTTGATAGTTTGAGATATTTGTCTATAAATGATATTTCTCAGCTCAAAGA
		TCGTGTAAATAATTATATTCCTTTGCTCAATGGGTTTATTTCTAATGAGGCTGCCAGTTCTGAGAGAT
		TCTATAATATCACTTTTAAATAACATAAACAGGGATTACAACTATGTAAAAAGAAATGCATATGGACA
		AAGACTGGGAACACAGATAATTGAAATCAGTTGTGTTAGGGTGGTGGAATTATGTGAATTTTTTTTTC
		TTTTTAAAATTTTATTTGATATTGTTATAATATTGCTTTACAATAAATAAACAGCAGAAAGGGAACTA
		TAGACACATAGAAAAGATGCCAGAAGCAGATGCCTTCTGGCCAGAGCGCAGAGCATGCAGGGCAGAGA
		TATTTGCTAGTTACAATTATTCCATAGGCTTTATGCTTGCCTGGGTGCTGAGGTTGGCACACGCTCGG
		GTATGGCACACGCTTTCTTAGGAGACTATTATCTATAAGTTAAAGCTAGGGAGATGTCACTATTAGAA
		CTCCAAACACACTCTTCTGCTTTAAAACAGGTTGTCTGCCCTCTGCTTTGGTATGGCATTCGGGTGTC
		TGTTTTGTGGTTGCTTTAGATTGGAGGGGTGACCATTTTATTAGCCCCCTTGATAACATCTGTTGCAG
		ATATTGCCTTTCTGGAACGTTTTAACAGACTCTCAGGTTGAATTTTGGAGGACTAGAAGGATAAAATC
		CCCAGCTCCCACCATTTTCTTGTCCAACAGGATATTACTGTATATCATTCAGGTAGGATTCTTCTTTT
		AATAACCAATAGGGCAAGTCCCACTAATTTCAATAGAAGTTATGACTTGCAATTAAAAGCTGACTTTG
		AAATCATTAAACAAATATGTAGGACTGTCTCTGCCTGTTGGCATTCAGTTATAGTTCTGTTAATTTTG
		GCTTGGGATGGTCTCCATGTGCTTTTTTCTGCCTATTTATAGGTTGTTTGCAGTAGTTGTGATTTTTA
		AAGAGCAAGGGAGACCATCTAACCAAAGGATAACTTCCTTCTAACTCACCAAAGAAATTTTAGGTGAG
		AACTTTAATAATGAGGTAGTCACCTCAGATATGCTGCTTAGTTTCACTAAAAGCAGACCCTATACCTA
		GAGAAGTCACTGGCTTTTTATTGGTCATTCTCAATACAGAAATACTTAGGGGAGTCTTAACCCTGCCA
		TCCCCGGTTGAATCTCTTGGTCTTTATCTAAGCTACTTGCAGTTAATATTCAGTTAAGCAAAGGTATG
		GCCAGTAGTGCAAGTATCTCCCAGTCTCTGAGCTCTGAACAAGAGGACTGAAATTCAGCATTTGTAAA
		CTGACAGTTTGATGGGCCTGGGATTTGAAGTGAACTCAGCACACAATTCTGAACGTGTATTTGCATGT
		GGACTGGGAAGGAAATAAATGGGAACTTGGAAATAATGGAATATTTCTCCTATGAAAGAATTTTTCGT
		AGAAGATTTGTTTTTGATATAATCTTTCTGTTGGTTAGCTTTTAGTGTTTTCATTCCTTTTCTGATCC
		ACACTCCTTTAAGTGACCAAATGAATATAACCCAACATGCATTGGGAATGTGTTTAATATTAAACAAT
		GTCTAACTGAATCTGCAAATGCGGGAACTGAGATATCACCTCCATGTGCACACCTGTGTGTACGAGTA
		TTCTATACAACTTGTAGCATTTACTGCCACTTAATTGGGTTGAACTTGCAAGATAAACTTTTGGAAAC
		TGCTTAGTGCCATCGGAGTCTCCTTTAGAAGCTGCCATCAGGCAAATGCTATCCCATAATACCAGCAG
		TAAGCCTGGCAACATGTTCAACAGATTTAGTACCCAAGAGGAAATCAACAGCGATAGTAGAGAATGAG
		TCAGATGTAGTGGGATAAATACTAGCCTAGGAAGAAGGAGCCCCGGAGTCTAATATGAGCTTTATTAC
		TAAATTGCTATGTGACGCTAGGCAAGTCACTTAACCTCTCCATGGCTGTTTCCTCATCTGTAAAATAA
		GTGTATTGGACTAGATGATCCTTAGGGTCTTTCCAAAAGTCTAACATTCTATGGCATTATAGGTTGCC
		TTGCAAATTCAGCCTGCTATAGTGATGGCAAATATCACGTTTAAGCCTGAGTCTCTTATGTTGCAGTT
		AAATAAAAGAACTATGTAAGATGATTTTTAAAATTCAAGCAAATGGGCCGGGTGCGGTGGCTCATACC
		TGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGCGGATCACCTGAGGTCAGGAGTTCGAGACCAGCCT
		GACCAACATAGAGAAACCCCATCTCTACTAAAAATACAAAATTAGCCGGGTGTGGTGGCGGGCGCCTG
		TAATCCCAGCTACTTGGGAGGCTGAGGTGGGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGTGGTGA
		GCTGAGATCATGCCATTGCACTCCAGCCTCGGCAACAAGAGTGAAACTTCGTCTCCAAAAAAAAAAAC
		TCAAGCAAATGAAGTTCATAATAATAGGGGATGTTGATAAAACTTGTGGCAGCCTTCCAATTCATTTA
		CAGTTGTTTCGTTTTGTTTTTGTTTTAATGTCCATTTTCTGTTGACTGTTCCCAGTTTTCATTTTCCA
		TACAGTCTGTATGTAAAGTCTGGTTTTCATTAAGCTGTGGCCAGTATTTGCCACTACAACAGAAACAC
		ACTGTCACACTTGCTAGAATATAACTGTACTTGAGCTTCTCCTTTCCTGTGAAGTAGTGCTGGGCTTT
		CTAGAGTTTAATTCTCAAGTGGCACAAGATAGCAGAGCCCATGCATTTTAATGGCTGAGACTGCTAAG
		AGTGAACCTAAACACTTACAAGTTGCAGAGAGAAATGAAAAAGTAATTACATGCTATTAGCATTGAGA
		AATGTTGACAAATTAATTTGTTGGGAACCAAAGATAGCATTTCTGATGACAACTCCCACAGTGATTGG
		CCAGTTGTATGATGAGTACACTGCTGGAAAGAGGGTAAACTGGGAGTTAGTGGATGGTCCCAATGCCC
		TGCCTACAGCAGAGTGCCAACCAGCCCTGAGTGCAAAATTCAAGTTCAATGTGTGTGCTTGTGTGTGG
		TGTGCTTTATGGACCCGCAAATACCATATTCATTATTGATGATAAGATCTTCACAGAATCCTGTAGCT
		ACTAATGCATTGAGTTTTTAATCTCAGTACATCAGCCAGGAGGAGCCAGATCACAGGGTAGTGATGTC
		TACTGGGATTATACTCATAACATCTACACAAAACAAGTTGAGAAGGATCCACGTTTTCATTGTTTATC
		AGAATTGTATCTCATTTGGCTGAGCATTACTTTTGTCAGAATGTGTTATCTGTAAACCATGTGTAGTG
		AAATTCTTCTGTAACTTTGGATTAAAGGTATTTATGGTCTTTTTGTTTGTTTGATTTTTAAGTAAGTT
		ATTTCTTTTGTAGACCTGCTGATGGTATGGTTCCATCCTTCTGACCTCAGCATCCAATCTTTTTAAGG
		ATTTTTGTTTTCAATATTGTTATTTTAAATTGTGGTTGAAGCAATAGAAAATTGAAATATGGATTGTG
		CATGACTGTGTCTTGAGTGTAAAAATATTGCAGTTTGAAACTTGGACCTAAAGTATTGCAAATAAAAA
		TGACAAACATCAATGA

7189	Human PAK3	AGAGCATCCTCAGCAGCTGCCACCGAAGCAGCCTCCTCCTTCTCTCTTCCTCCTCCTCCTACCACGGC
	transcript	CGCCGCCACCACCGCTGCGGCTGTGATCTCCTATCCCCTCTGGTCCTCCTTCCTCCCCCAGTTCCTGC
	variant	TCCTCCTCCCATCCCCTGCTCCTCCTGCCCAGCAGCGAAGGGCAGAACCCTCGGCTGCCGCCCTCCTT
	3 mRNA	CGCTCTGACCAAGAAGAGGCTGGAACAGGAGCTGTGAAATTAGTTGTAACTGAAAATGTCTGACGGTC
	NM_001128167.	TGGATAATGAAGAGAAACCCCCGGCTCCTCCACTGAGGATGAATAGTAACAACCGGGATTCTTCAGCA
	3	CTCAACCACAGCTCCAAACCACTTCCCATGGCCCCTGAAGAGAAGAATAAGAAAGCCAGGCTTCGCTC
	(GI:1890283404	TATCTTCCCAGGAGGAGGGGATAAAACCAATAAGAAGAAGGAGAAAGAGCGCCCAGAGATCTCTCTTC
	version 3)	CTTCAGACTTTGAGCATACGATTCATGTGGGGTTTGATGCAGTCACCGGGGAATTCACTGGAATTCCA
		GAGCAATGGGCACGATTACTCCAAACTTCCAACATAACAAAATTGGAACAGAAGAAGAACCCACAAGC
		TGTTCTAGATGTTCTCAAATTCTATGATTCCAAAGAAACAGTCAACAACCAGAAATACATGAGCTTTA
		CATCAGGAGATAAAAGTGCACATGGATACATAGCAGCCCATCCTTCGAGTACAAAAACAGCATCTGAG
		CCTCCATTGGCCCCTCCTGTGTCTGAAGAAGAAGATGAAGAGGAAGAAGAAGAAGAAGATGAAAATGA
		GCCACCACCAGTTATCGCACCAAGACCAGAGCATACAAAATCAATCTATACTCGTTCTGTGGTTGAAT
		CCATTGCTTCACCAGCAGTACCAAATAAAGAGGTCACACCACCCTCTGCTGAAAATGCCAATTCCAGT
		ACTTTGTACAGGAACACAGATCGGCAAAGAAAAAAATCCAAGATGACAGATGAGGAGATCTTAGAGAA
		GCTAAGAAGCATTGTGAGTGTTGGGGACCCAAAGAAAAAATACACAAGATTTGAAAAAATTGGTCAAG
		GGGCATCAGGTACTGTTTATACAGCACTAGACATTGCAACAGGACAAGAGGTGGCCATAAAGCAGATG
		AACCTTCAACAGCAACCCAAGAAGGAATTAATTATTAATGAAATTCTGGTCATGAGGGAAAATAAGAA
		CCCTAATATTGTTAATTATTTAGATAGCTACTTGGTGGGTGATGAACTATGGGTAGTCATGGAATACT
		TGGCTGGTGGCTCTCTGACTGATGTGGTCACAGAGACCTGTATGGATGAAGGACAGATAGCAGCTGTC
		TGCAGAGAGTGCCTGCAAGCTTTGGATTTCCTGCACTCAAACCAGGTGATCCATAGAGATATAAAGAG
		TGACAATATTCTTCTCGGGATGGATGGCTCTGTTAAATTGACTGACTTTGGGTTCTGTGCCCAGATCA
		CTCCTGAGCAAAGTAAACGAAGCACTATGGTGGGAACCCCATATTGGATGGCACCTGAGGTGGTGACT
		CGAAAAGCTTATGGTCCGAAAGTTGATATCTGGTCTCTTGGAATTATGGCAATTGAAATGGTGGAAGG
		TGAACCCCCTTACCTTAATGAAAATCCACTCAGGGCATTGTATCTGATAGCCACTAATGGAACTCCAG
		AGCTCCAGAATCCTGAGAGACTGTCAGCTGTATTCCGTGACTTTTTAAATCGCTGTCTTGAGATGGAT
		GTGGATAGGCGAGGATCTGCCAAGGAGCTTTTGCAGCATCCATTTTTAAAATTAGCCAAGCCTCTCTC
		CAGCCTGACTCCTCTGATTATCGCTGCAAAGGAAGCAATTAAGAACAGCAGCCGCTAAGACTGCAAGC
		CTTACACCTCACCATCTCCCTCATGAGTAAGACTGAAATAAAACTCTGCTGCAGGAAAGATGGAAGAA
		AAGACAGTCAAATGGGGTGGGGGTTCTTTACCTTTCAAATGAATAGAAACTTCTTATAAGCCTTTTTC
		CTACTCCCTCAGATTATGTAATTTATTTGTAAGCCTGAATCGCAGCCCAAACAGGGCAGCAATGTTGA
		AGTGACCATAAAGTGGTCACTTCCACCGTGAAGCGAAAGAGCCAGTAGTGAATCCCCTCATTTTGTGC
		ATTCACTTTGAAGAAAAAGGTTTCTCAAAGATGCACACTCCCTCTTCATAGTGTTGTGTTTGTTTTTA
		AGTTAGAGAGTAGTCCCTCTTGCATTCAAACCTCCTTCAAAACTCCTTACCCAATGTGATGTTTTTCA
		CTTGCATTGTCATTAGATGTCCAGAAAAAAAAAAGATGTCAAAATGTTTTTCTAAAAAAAGAAAGCAA
		AAAAAGCAAGGCAAAAAAAAAAAAAAAAACAAACAAAAACAAAAACAAAACAAAAACAAGCAAACAAA
		AAATACCAGAGCAAGTACTGTGTGAACATGTGGAAGTCCATGCCCTAATAGAGTTGCAATTTTTTATT
		CTTCTTCTATAGTGGTGGCTTGGTTTGTGTACCTATTTTTCTGCATTTGTATTGGAAAAGGTTTCTTT
		TAAGACATTTTCCAAAAGTGGAGAGGAATATGTGTGTTCAGGAAGGGCTTTCAAAAAACTGTATATCT
		AAATAAAGCTCAAACGGTGAAATCCTGTCACATTTTCACAATGATGCTTAAAAGATAATTGAGTAAAC
		CAGGTTGTTAATCTCCTTAATACCTGAAAGAGGACACACTGAAACTGAAACTGTGACATCCTGCTAGG
		TGAGTTCAGGTTCTGAACCTAGGAAATCCTCATAGGAGAAACCACATTTAAACAAAGATGGGACTTTC
		TCTGAGAGCCAAAACCAGATAAATGTAGAATACTGAAATCCTTGTTGGACATTAAGTAAACAAAGATA
		ATGATACCTAAATTAATCCTCTCTTGTGCTTATGAAACATATGCACTGTAAAATAGGCATACCAGGAG
		GAAATAGATACATTAATCATCATTTACTTATGATACAAATTATTTATTTTGACAATTTATAACGTTTA
		AAAAAGTTTTTTAAAGATCTAGAGAAAGGTGATATAGTAAACATTCAACTCTGTAAGAAATGGGAGGT
		CAGTGAAGGCTACATCCCAATCAATATTTGGCTCTAAGTACCTCTTCCCATTTTTCCTATGTATCACC
		TATTTCTGTTTCGGAATATGGTGTGTTCATGCTTAGTTCTTTGGGCTTTTGAATATCAAAAGCATATT
		CATAAATGTCTTGAAATTCTCTCCAGTGGAAAATAATTTTAACTTACAATCATATCCCAAGAAATGTC
		AGTCCGACAGAATTCCTTATATGACTTGGGGAAAATAACAAAATTTGACTACTATTTCACCATATATC
		TATTTATTAAAAAATTCAACAGTTGGCACTTCCTGAATCTTCTGAGAGTAGAAAAATATCTGCGGAGT
		GTCTGTGTAGAAAAGGATATGCCTCTCTTTTGAGTGTATTGACAATTTTGTAAATTACAGAAAGTTGT
		TTCTCTAAGCCTTTGAAAAACTAACAATTTGTGTTATAGAAGGCTTCTTAATTTGCAGTATAAAAGAA
		TCTAAACAGAACTTATGTACATTCAGCCAGAAGGGGAAAGAGATCAGTTACATAGGCCTCTCTCCTTC
		TTTGCCAAGGTACATCCATCCATCTAACCATCCATATATCCACATCTTAAAATGAAAGCACTTTCTTT
		AGAGTTTCAGCAAACTATATAGTGTACGTGTTTATGTTCAGGAGATGACCCCACTGGTGTATTTCCTA
		TTTTCCCTATTGTTTTCTTTGACTGTAAAAGTTGGGAGAGGCTTGACCTCCTCCCCTTGAAAATGTCC
		ACAGTGGGATAAAACAACAAATGTGAAAAGAAAATGAAACGGTAATATTAATTTGAAGCATACTATGT
		TATACTTTGCAAAAACGAATCTGGGCCTGTAATTTTTAATGCCACACTGCTCTAATGAGAGAGAGAGG
		CCTTAATTTTGATTTCATTTAAAAATAAGTACTTTAAAAAATTTTTCACTCATAGTGCCGGGAAATTC
		AATGAAATCCTGGGATGCAAATAAAAATCAGTACATTAGTGACTGTGTCCTGCCAGTGGAGAGAGCCC
		AATACCTGGTTAGGAAGCCCTATTCATTAGTTAGCATCCCTTACATGTTGAGAAGGCCTTTTTTTTGT
		TGTTATTTTGGAGACCTTGGAGCAGTGACCCTTCAGATCACTGTAGGCAGAGAAATGGCTTCTCTCTT
		ATGCTTTCAGTTCAGCATATTAACAATGAGGAGCCAGGTACTTCTTTACTACCACTTTGTACCAAGAT
		TTGATAATAATATATCCCAGGAGGCATTACTTTTATAAATTTGTATTCATGTAAATTTTCAAATGAGA
		ACAGCTTCTAAAGCCCCTTCCCTGTATTGGAGAGTTATGTATATTTCTAATAAGTATTAGAAAGAAGC
		TGTTTCTCATGCCACAGTGATGCTGAAGGATTCACATTTGGTACAATCGAGTAACTTGAACGCCAGAT
		TGTTAACAGTTTATTCTCTTTCCCTGGATTTTTAAGCTCATCTTGACACAGGTGAGTCTATCCAAATC
		TTTGATGTTGCTAGTGTGCCCTGAGATAACGAGGGCACATCTTTCAATGTTGATTCCAAAATGTCCTG
		AGTTAGGAATAGGGCAGTGGGAAAGTCAGGGAAGGGTGAGAAGCACAGTAGAGATTATTTATTTAAAA
		AAGGAAAGAACGTTAATGTTGTTAGCAAGGATCCAGTGCGTTGTCATAATCCCATGAGGATTTTCAGA
		TGACACAATCCCCTCAAATCAGTCACCATGTTGGGTAATGACTTCGTTCTTGCTGATCTCGTGTGTGT
		GTCATTGTAAATATTTGTGTGTCCATGTTCCATTTTGGCTACTGGATGGCCAAGCCATGTAAGAAGAT
		TTAACTCAAGTATTTATTCTTTATGTTATTCAGATTTCTTTCAGGCTTGTGAACTGCACCCCAATGTT
		TGAGTTTAACCACCTGATCCTTACATCTATCCCTCCCCGGTGAAGCACATTCCATTGCTAAAAGAAAA
		AGAAACACGAAATTGCTTCCTGTTGTCTGTATAACTGTTTTGATAGTTTGAGATATTTGTCTATAAAT
		GATATTTCTCAGCTCAAAGATCGTGTAAATAATTATATTCCTTTGCTCAATGGGTTTATTTCTAATGA
		GGCTGCCAGTTCTGAGAGATTCTATAATATCACTTTTAAATAACATAAACAGGGATTACAACTATGTA
		AAAAGAAATGCATATGGACAAAGACTGGGAACACAGATAATTGAAATCAGTTGTGTTAGGGTGGTGGA
		ATTATGTGAATTTTTTTTTCTTTTTAAAATTTTATTTGATATTGTTATAATATTGCTTTACAATAAAT
		AAACAGCAGAAAGGGAACTATAGACACATAGAAAAGATGCCAGAAGCAGATGCCTTCTGGCCAGAGCG
		CAGAGCATGCAGGGCAGAGATATTTGCTAGTTACAATTATTCCATAGGCTTTATGCTTGCCTGGGTGC
		TGAGGTTGGCACACGCTCGGGTATGGCACACGCTTTCTTAGGAGACTATTATCTATAAGTTAAAGCTA
		GGGAGATGTCACTATTAGAACTCCAAACACACTCTTCTGCTTTAAAACAGGTTGTCTGCCCTCTGCTT
		TGGTATGGCATTCGGGTGTCTGTTTTGTGGTTGCTTTAGATTGGAGGGGTGACCATTTTATTAGCCCC
		CTTGATAACATCTGTTGCAGATATTGCCTTTCTGGAACGTTTTAACAGACTCTCAGGTTGAATTTTGG
		AGGACTAGAAGGATAAAATCCCCAGCTCCCACCATTTTCTTGTCCAACAGGATATTACTGTATATCAT
		TCAGGTAGGATTCTTCTTTTAATAACCAATAGGGCAAGTCCCACTAATTTCAATAGAAGTTATGACTT
		GCAATTAAAAGCTGACTTTGAAATCATTAAACAAATATGTAGGACTGTCTCTGCCTGTTGGCATTCAG
		TTATAGTTCTGTTAATTTTGGCTTGGGATGGTCTCCATGTGCTTTTTTCTGCCTATTTATAGGTTGTT
		TGCAGTAGTTGTGATTTTTAAAGAGCAAGGGAGACCATCTAACCAAAGGATAACTTCCTTCTAACTCA
		CCAAAGAAATTTTAGGTGAGAACTTTAATAATGAGGTAGTCACCTCAGATATGCTGCTTAGTTTCACT
		AAAAGCAGACCCTATACCTAGAGAAGTCACTGGCTTTTTATTGGTCATTCTCAATACAGAAATACTTA
		GGGGAGTCTTAACCCTGCCATCCCCGGTTGAATCTCTTGGTCTTTATCTAAGCTACTTGCAGTTAATA
		TTCAGTTAAGCAAAGGTATGGCCAGTAGTGCAAGTATCTCCCAGTCTCTGAGCTCTGAACAAGAGGAC
		TGAAATTCAGCATTTGTAAACTGACAGTTTGATGGGCCTGGGATTTGAAGTGAACTCAGCACACAATT
		CTGAACGTGTATTTGCATGTGGACTGGGAAGGAAATAAATGGGAACTTGGAAATAATGGAATATTTCT
		CCTATGAAAGAATTTTTCGTAGAAGATTTGTTTTTGATATAATCTTTCTGTTGGTTAGCTTTTAGTGT
		TTTCATTCCTTTTCTGATCCACACTCCTTTAAGTGACCAAATGAATATAACCCAACATGCATTGGGAA
		TGTGTTTAATATTAAACAATGTCTAACTGAATCTGCAAATGCGGGAACTGAGATATCACCTCCATGTG
		CACACCTGTGTGTACGAGTATTCTATACAACTTGTAGCATTTACTGCCACTTAATTGGGTTGAACTTG
		CAAGATAAACTTTTGGAAACTGCTTAGTGCCATCGGAGTCTCCTTTAGAAGCTGCCATCAGGCAAATG
		CTATCCCATAATACCAGCAGTAAGCCTGGCAACATGTTCAACAGATTTAGTACCCAAGAGGAAATCAA
		CAGCGATAGTAGAGAATGAGTCAGATGTAGTGGGATAAATACTAGCCTAGGAAGAAGGAGCCCCGGAG
		TCTAATATGAGCTTTATTACTAAATTGCTATGTGACGCTAGGCAAGTCACTTAACCTCTCCATGGCTG
		TTTCCTCATCTGTAAAATAAGTGTATTGGACTAGATGATCCTTAGGGTCTTTCCAAAAGTCTAACATT
		CTATGGCATTATAGGTTGCCTTGCAAATTCAGCCTGCTATAGTGATGGCAAATATCACGTTTAAGCCT
		GAGTCTCTTATGTTGCAGTTAAATAAAAGAACTATGTAAGATGATTTTTAAAATTCAAGCAAATGGGC
		CGGGTGCGGTGGCTCATACCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGCGGATCACCTGAGGT
		CAGGAGTTCGAGACCAGCCTGACCAACATAGAGAAACCCCATCTCTACTAAAAATACAAAATTAGCCG
		GGTGTGGTGGCGGGCGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGTGGGAGAATCGCTTGAACCCA
		GGAGGCGGAGGTTGTGGTGAGCTGAGATCATGCCATTGCACTCCAGCCTCGGCAACAAGAGTGAAACT
		TCGTCTCCAAAAAAAAAAACTCAAGCAAATGAAGTTCATAATAATAGGGGATGTTGATAAAACTTGTG
		GCAGCCTTCCAATTCATTTACAGTTGTTTCGTTTTGTTTTTGTTTTAATGTCCATTTTCTGTTGACTG
		TTCCCAGTTTTCATTTTCCATACAGTCTGTATGTAAAGTCTGGTTTTCATTAAGCTGTGGCCAGTATT
		TGCCACTACAACAGAAACACACTGTCACACTTGCTAGAATATAACTGTACTTGAGCTTCTCCTTTCCT
		GTGAAGTAGTGCTGGGCTTTCTAGAGTTTAATTCTCAAGTGGCACAAGATAGCAGAGCCCATGCATTT
		TAATGGCTGAGACTGCTAAGAGTGAACCTAAACACTTACAAGTTGCAGAGAGAAATGAAAAAGTAATT
		ACATGCTATTAGCATTGAGAAATGTTGACAAATTAATTTGTTGGGAACCAAAGATAGCATTTCTGATG
		ACAACTCCCACAGTGATTGGCCAGTTGTATGATGAGTACACTGCTGGAAAGAGGGTAAACTGGGAGTT
		AGTGGATGGTCCCAATGCCCTGCCTACAGCAGAGTGCCAACCAGCCCTGAGTGCAAAATTCAAGTTCA
		ATGTGTGTGCTTGTGTGTGGTGTGCTTTATGGACCCGCAAATACCATATTCATTATTGATGATAAGAT
		CTTCACAGAATCCTGTAGCTACTAATGCATTGAGTTTTTAATCTCAGTACATCAGCCAGGAGGAGCCA
		GATCACAGGGTAGTGATGTCTACTGGGATTATACTCATAACATCTACACAAAACAAGTTGAGAAGGAT
		CCACGTTTTCATTGTTTATCAGAATTGTATCTCATTTGGCTGAGCATTACTTTTGTCAGAATGTGTTA
		TCTGTAAACCATGTGTAGTGAAATTCTTCTGTAACTTTGGATTAAAGGTATTTATGGTCTTTTTGTTT
		GTTTGATTTTTAAGTAAGTTATTTCTTTTGTAGACCTGCTGATGGTATGGTTCCATCCTTCTGACCTC
		AGCATCCAATCTTTTTAAGGATTTTTGTTTTCAATATTGTTATTTTAAATTGTGGTTGAAGCAATAGA
		AAATTGAAATATGGATTGTGCATGACTGTGTCTTGAGTGTAAAAATATTGCAGTTTGAAACTTGGACC
		TAAAGTATTGCAAATAAAAATGACAAACATCAATGA

7190	Human PAK3	ACCGCGGGCGGGCAGCTGTGCCAGCTAACCGTCTGGGATCTCGCACTGGGGGCTGCAGCTTTTCCCCG
	transcript	CCTCGAGCCAGTGTGCGGGGGCGGGAGAAGAGCCAGGGGGAGCGGGCTGGGCCCGGGGCTGCGGCTGC
	variant	GGCCGCGGGGCTGCGGCTCCCCAGCCCCGCCAGCTGGAGCGCTCGGAGGTAGAGGAAAGGTCTTGACG
	4 mRNA	GGGTGGCTGGATCCGTGGCAGAATCCAGTTCCAGATTCTAGACTTGAGGGTTCTGGGCTGTTGGTCTG
	NM_001128168.	TAGAAGCGAAGGAGAGAAGGACTCAAATCCAGGCCAAGTGTATGGCTGTCTGAGGTATTGGAACAGAA
	3	GGAGGTCCATTCCTGTTGGTGACAACACCGTGGCCCTGTTCTGGGATGAGCAAGGTGTAAAGCAGGTT
	(GI:1676441496	TCCCCCAAGAAAGAGCAGCTGAGTCCTTGCATCTTGTGGCAGCTGGTGTGCCCAGCACTGAGTCTGTA
	version 3)	GGAGCTGAAGCCAGCCCGGACCCTTCTCATGGGCAGTGCCCACCTGTGCTGAAGTCCTGCAGCGGTGG
		CGGTGTGAGGAGCTGTGAAATTAGTTGTAACTGAAAATGTCTGACGGTCTGGATAATGAAGAGAAACC
		CCCGGCTCCTCCACTGAGGATGAATAGTAACAACCGGGATTCTTCAGCACTCAACCACAGCTCCAAAC
		CACTTCCCATGGCCCCTGAAGAGAAGAATAAGAAAGCCAGGCTTCGCTCTATCTTCCCAGGAGGAGGG
		GATAAAACCAATAAGAAGAAGGAGAAAGAGCGCCCAGAGATCTCTCTTCCTTCAGACTTTGAGCATAC
		GATTCATGTGGGGTTTGATGCAGTCACCGGGGAATTCACTAACTCCCCTTTCCAGACCTCTAGACCTG
		TGACGGTCGCTTCAAGTCAATCAGAGGGAAAAATGCCAGATCTCTATGGCTCACAGATGTGCCCAGGG
		AAGCTCCCAGAGGGAATTCCAGAGCAATGGGCACGATTACTCCAAACTTCCAACATAACAAAATTGGA
		ACAGAAGAAGAACCCACAAGCTGTTCTAGATGTTCTCAAATTCTATGATTCCAAAGAAACAGTCAACA
		ACCAGAAATACATGAGCTTTACATCAGGAGATAAAAGTGCACATGGATACATAGCAGCCCATCCTTCG
		AGTACAAAAACAGCATCTGAGCCTCCATTGGCCCCTCCTGTGTCTGAAGAAGAAGATGAAGAGGAAGA
		AGAAGAAGAAGATGAAAATGAGCCACCACCAGTTATCGCACCAAGACCAGAGCATACAAAATCAATCT
		ATACTCGTTCTGTGGTTGAATCCATTGCTTCACCAGCAGTACCAAATAAAGAGGTCACACCACCCTCT
		GCTGAAAATGCCAATTCCAGTACTTTGTACAGGAACACAGATCGGCAAAGAAAAAAATCCAAGATGAC
		AGATGAGGAGATCTTAGAGAAGCTAAGAAGCATTGTGAGTGTTGGGGACCCAAAGAAAAAATACACAA
		GATTTGAAAAAATTGGTCAAGGGGCATCAGGTACTGTTTATACAGCACTAGACATTGCAACAGGACAA
		GAGGTGGCCATAAAGCAGATGAACCTTCAACAGCAACCCAAGAAGGAATTAATTATTAATGAAATTCT
		GGTCATGAGGGAAAATAAGAACCCTAATATTGTTAATTATTTAGATAGCTACTTGGTGGGTGATGAAC
		TATGGGTAGTCATGGAATACTTGGCTGGTGGCTCTCTGACTGATGTGGTCACAGAGACCTGTATGGAT
		GAAGGACAGATAGCAGCTGTCTGCAGAGAGTGCCTGCAAGCTTTGGATTTCCTGCACTCAAACCAGGT
		GATCCATAGAGATATAAAGAGTGACAATATTCTTCTCGGGATGGATGGCTCTGTTAAATTGACTGACT
		TTGGGTTCTGTGCCCAGATCACTCCTGAGCAAAGTAAACGAAGCACTATGGTGGGAACCCCATATTGG
		ATGGCACCTGAGGTGGTGACTCGAAAAGCTTATGGTCCGAAAGTTGATATCTGGTCTCTTGGAATTAT
		GGCAATTGAAATGGTGGAAGGTGAACCCCCTTACCTTAATGAAAATCCACTCAGGGCATTGTATCTGA
		TAGCCACTAATGGAACTCCAGAGCTCCAGAATCCTGAGAGACTGTCAGCTGTATTCCGTGACTTTTTA
		AATCGCTGTCTTGAGATGGATGTGGATAGGCGAGGATCTGCCAAGGAGCTTTTGCAGCATCCATTTTT
		AAAATTAGCCAAGCCTCTCTCCAGCCTGACTCCTCTGATTATCGCTGCAAAGGAAGCAATTAAGAACA
		GCAGCCGCTAAGACTGCAAGCCTTACACCTCACCATCTCCCTCATGAGTAAGACTGAAATAAAACTCT
		GCTGCAGGAAAGATGGAAGAAAAGACAGTCAAATGGGGTGGGGGTTCTTTACCTTTCAAATGAATAGA
		AACTTCTTATAAGCCTTTTTCCTACTCCCTCAGATTATGTAATTTATTTGTAAGCCTGAATCGCAGCC
		CAAACAGGGCAGCAATGTTGAAGTGACCATAAAGTGGTCACTTCCACCGTGAAGCGAAAGAGCCAGTA
		GTGAATCCCCTCATTTTGTGCATTCACTTTGAAGAAAAAGGTTTCTCAAAGATGCACACTCCCTCTTC
		ATAGTGTTGTGTTTGTTTTTAAGTTAGAGAGTAGTCCCTCTTGCATTCAAACCTCCTTCAAAACTCCT
		TACCCAATGTGATGTTTTTCACTTGCATTGTCATTAGATGTCCAGAAAAAAAAAAGATGTCAAAATGT
		TTTTCTAAAAAAAGAAAGCAAAAAAAGCAAGGCAAAAAAAAAAAAAAAAACAAACAAAAACAAAAACA
		AAACAAAAACAAGCAAACAAAAAATACCAGAGCAAGTACTGTGTGAACATGTGGAAGTCCATGCCCTA
		ATAGAGTTGCAATTTTTTATTCTTCTTCTATAGTGGTGGCTTGGTTTGTGTACCTATTTTTCTGCATT
		TGTATTGGAAAAGGTTTCTTTTAAGACATTTTCCAAAAGTGGAGAGGAATATGTGTGTTCAGGAAGGG
		CTTTCAAAAAACTGTATATCTAAATAAAGCTCAAACGGTGAAATCCTGTCACATTTTCACAATGATGC
		TTAAAAGATAATTGAGTAAACCAGGTTGTTAATCTCCTTAATACCTGAAAGAGGACACACTGAAACTG
		AAACTGTGACATCCTGCTAGGTGAGTTCAGGTTCTGAACCTAGGAAATCCTCATAGGAGAAACCACAT
		TTAAACAAAGATGGGACTTTCTCTGAGAGCCAAAACCAGATAAATGTAGAATACTGAAATCCTTGTTG
		GACATTAAGTAAACAAAGATAATGATACCTAAATTAATCCTCTCTTGTGCTTATGAAACATATGCACT
		GTAAAATAGGCATACCAGGAGGAAATAGATACATTAATCATCATTTACTTATGATACAAATTATTTAT
		TTTGACAATTTATAACGTTTAAAAAAGTTTTTTAAAGATCTAGAGAAAGGTGATATAGTAAACATTCA
		ACTCTGTAAGAAATGGGAGGTCAGTGAAGGCTACATCCCAATCAATATTTGGCTCTAAGTACCTCTTC
		CCATTTTTCCTATGTATCACCTATTTCTGTTTCGGAATATGGTGTGTTCATGCTTAGTTCTTTGGGCT
		TTTGAATATCAAAAGCATATTCATAAATGTCTTGAAATTCTCTCCAGTGGAAAATAATTTTAACTTAC
		AATCATATCCCAAGAAATGTCAGTCCGACAGAATTCCTTATATGACTTGGGGAAAATAACAAAATTTG
		ACTACTATTTCACCATATATCTATTTATTAAAAAATTCAACAGTTGGCACTTCCTGAATCTTCTGAGA
		GTAGAAAAATATCTGCGGAGTGTCTGTGTAGAAAAGGATATGCCTCTCTTTTGAGTGTATTGACAATT
		TTGTAAATTACAGAAAGTTGTTTCTCTAAGCCTTTGAAAAACTAACAATTTGTGTTATAGAAGGCTTC
		TTAATTTGCAGTATAAAAGAATCTAAACAGAACTTATGTACATTCAGCCAGAAGGGGAAAGAGATCAG
		TTACATAGGCCTCTCTCCTTCTTTGCCAAGGTACATCCATCCATCTAACCATCCATATATCCACATCT
		TAAAATGAAAGCACTTTCTTTAGAGTTTCAGCAAACTATATAGTGTACGTGTTTATGTTCAGGAGATG
		ACCCCACTGGTGTATTTCCTATTTTCCCTATTGTTTTCTTTGACTGTAAAAGTTGGGAGAGGCTTGAC
		CTCCTCCCCTTGAAAATGTCCACAGTGGGATAAAACAACAAATGTGAAAAGAAAATGAAACGGTAATA
		TTAATTTGAAGCATACTATGTTATACTTTGCAAAAACGAATCTGGGCCTGTAATTTTTAATGCCACAC
		TGCTCTAATGAGAGAGAGAGGCCTTAATTTTGATTTCATTTAAAAATAAGTACTTTAAAAAATTTTTC
		ACTCATAGTGCCGGGAAATTCAATGAAATCCTGGGATGCAAATAAAAATCAGTACATTAGTGACTGTG
		TCCTGCCAGTGGAGAGAGCCCAATACCTGGTTAGGAAGCCCTATTCATTAGTTAGCATCCCTTACATG
		TTGAGAAGGCCTTTTTTTTGTTGTTATTTTGGAGACCTTGGAGCAGTGACCCTTCAGATCACTGTAGG
		CAGAGAAATGGCTTCTCTCTTATGCTTTCAGTTCAGCATATTAACAATGAGGAGCCAGGTACTTCTTT
		ACTACCACTTTGTACCAAGATTTGATAATAATATATCCCAGGAGGCATTACTTTTATAAATTTGTATT
		CATGTAAATTTTCAAATGAGAACAGCTTCTAAAGCCCCTTCCCTGTATTGGAGAGTTATGTATATTTC
		TAATAAGTATTAGAAAGAAGCTGTTTCTCATGCCACAGTGATGCTGAAGGATTCACATTTGGTACAAT
		CGAGTAACTTGAACGCCAGATTGTTAACAGTTTATTCTCTTTCCCTGGATTTTTAAGCTCATCTTGAC
		ACAGGTGAGTCTATCCAAATCTTTGATGTTGCTAGTGTGCCCTGAGATAACGAGGGCACATCTTTCAA
		TGTTGATTCCAAAATGTCCTGAGTTAGGAATAGGGCAGTGGGAAAGTCAGGGAAGGGTGAGAAGCACA
		GTAGAGATTATTTATTTAAAAAAGGAAAGAACGTTAATGTTGTTAGCAAGGATCCAGTGCGTTGTCAT
		AATCCCATGAGGATTTTCAGATGACACAATCCCCTCAAATCAGTCACCATGTTGGGTAATGACTTCGT
		TCTTGCTGATCTCGTGTGTGTGTCATTGTAAATATTTGTGTGTCCATGTTCCATTTTGGCTACTGGAT
		GGCCAAGCCATGTAAGAAGATTTAACTCAAGTATTTATTCTTTATGTTATTCAGATTTCTTTCAGGCT
		TGTGAACTGCACCCCAATGTTTGAGTTTAACCACCTGATCCTTACATCTATCCCTCCCCGGTGAAGCA
		CATTCCATTGCTAAAAGAAAAAGAAACACGAAATTGCTTCCTGTTGTCTGTATAACTGTTTTGATAGT
		TTGAGATATTTGTCTATAAATGATATTTCTCAGCTCAAAGATCGTGTAAATAATTATATTCCTTTGCT
		CAATGGGTTTATTTCTAATGAGGCTGCCAGTTCTGAGAGATTCTATAATATCACTTTTAAATAACATA
		AACAGGGATTACAACTATGTAAAAAGAAATGCATATGGACAAAGACTGGGAACACAGATAATTGAAAT
		CAGTTGTGTTAGGGTGGTGGAATTATGTGAATTTTTTTTTCTTTTTAAAATTTTATTTGATATTGTTA
		TAATATTGCTTTACAATAAATAAACAGCAGAAAGGGAACTATAGACACATAGAAAAGATGCCAGAAGC
		AGATGCCTTCTGGCCAGAGCGCAGAGCATGCAGGGCAGAGATATTTGCTAGTTACAATTATTCCATAG
		GCTTTATGCTTGCCTGGGTGCTGAGGTTGGCACACGCTCGGGTATGGCACACGCTTTCTTAGGAGACT
		ATTATCTATAAGTTAAAGCTAGGGAGATGTCACTATTAGAACTCCAAACACACTCTTCTGCTTTAAAA
		CAGGTTGTCTGCCCTCTGCTTTGGTATGGCATTCGGGTGTCTGTTTTGTGGTTGCTTTAGATTGGAGG
		GGTGACCATTTTATTAGCCCCCTTGATAACATCTGTTGCAGATATTGCCTTTCTGGAACGTTTTAACA
		GACTCTCAGGTTGAATTTTGGAGGACTAGAAGGATAAAATCCCCAGCTCCCACCATTTTCTTGTCCAA
		CAGGATATTACTGTATATCATTCAGGTAGGATTCTTCTTTTAATAACCAATAGGGCAAGTCCCACTAA
		TTTCAATAGAAGTTATGACTTGCAATTAAAAGCTGACTTTGAAATCATTAAACAAATATGTAGGACTG
		TCTCTGCCTGTTGGCATTCAGTTATAGTTCTGTTAATTTTGGCTTGGGATGGTCTCCATGTGCTTTTT
		TCTGCCTATTTATAGGTTGTTTGCAGTAGTTGTGATTTTTAAAGAGCAAGGGAGACCATCTAACCAAA
		GGATAACTTCCTTCTAACTCACCAAAGAAATTTTAGGTGAGAACTTTAATAATGAGGTAGTCACCTCA
		GATATGCTGCTTAGTTTCACTAAAAGCAGACCCTATACCTAGAGAAGTCACTGGCTTTTTATTGGTCA
		TTCTCAATACAGAAATACTTAGGGGAGTCTTAACCCTGCCATCCCCGGTTGAATCTCTTGGTCTTTAT
		CTAAGCTACTTGCAGTTAATATTCAGTTAAGCAAAGGTATGGCCAGTAGTGCAAGTATCTCCCAGTCT
		CTGAGCTCTGAACAAGAGGACTGAAATTCAGCATTTGTAAACTGACAGTTTGATGGGCCTGGGATTTG
		AAGTGAACTCAGCACACAATTCTGAACGTGTATTTGCATGTGGACTGGGAAGGAAATAAATGGGAACT
		TGGAAATAATGGAATATTTCTCCTATGAAAGAATTTTTCGTAGAAGATTTGTTTTTGATATAATCTTT
		CTGTTGGTTAGCTTTTAGTGTTTTCATTCCTTTTCTGATCCACACTCCTTTAAGTGACCAAATGAATA
		TAACCCAACATGCATTGGGAATGTGTTTAATATTAAACAATGTCTAACTGAATCTGCAAATGCGGGAA
		CTGAGATATCACCTCCATGTGCACACCTGTGTGTACGAGTATTCTATACAACTTGTAGCATTTACTGC
		CACTTAATTGGGTTGAACTTGCAAGATAAACTTTTGGAAACTGCTTAGTGCCATCGGAGTCTCCTTTA
		GAAGCTGCCATCAGGCAAATGCTATCCCATAATACCAGCAGTAAGCCTGGCAACATGTTCAACAGATT
		TAGTACCCAAGAGGAAATCAACAGCGATAGTAGAGAATGAGTCAGATGTAGTGGGATAAATACTAGCC
		TAGGAAGAAGGAGCCCCGGAGTCTAATATGAGCTTTATTACTAAATTGCTATGTGACGCTAGGCAAGT
		CACTTAACCTCTCCATGGCTGTTTCCTCATCTGTAAAATAAGTGTATTGGACTAGATGATCCTTAGGG
		TCTTTCCAAAAGTCTAACATTCTATGGCATTATAGGTTGCCTTGCAAATTCAGCCTGCTATAGTGATG
		GCAAATATCACGTTTAAGCCTGAGTCTCTTATGTTGCAGTTAAATAAAAGAACTATGTAAGATGATTT
		TTAAAATTCAAGCAAATGGGCCGGGTGCGGTGGCTCATACCTGTAATCCCAGCACTTTGGGAGGCCAA
		GGCAGGCGGATCACCTGAGGTCAGGAGTTCGAGACCAGCCTGACCAACATAGAGAAACCCCATCTCTA
		CTAAAAATACAAAATTAGCCGGGTGTGGTGGCGGGCGCCTGTAATCCCAGCTACTTGGGAGGCTGAGG
		TGGGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGTGGTGAGCTGAGATCATGCCATTGCACTCCAGC
		CTCGGCAACAAGAGTGAAACTTCGTCTCCAAAAAAAAAAACTCAAGCAAATGAAGTTCATAATAATAG
		GGGATGTTGATAAAACTTGTGGCAGCCTTCCAATTCATTTACAGTTGTTTCGTTTTGTTTTTGTTTTA
		ATGTCCATTTTCTGTTGACTGTTCCCAGTTTTCATTTTCCATACAGTCTGTATGTAAAGTCTGGTTTT
		CATTAAGCTGTGGCCAGTATTTGCCACTACAACAGAAACACACTGTCACACTTGCTAGAATATAACTG
		TACTTGAGCTTCTCCTTTCCTGTGAAGTAGTGCTGGGCTTTCTAGAGTTTAATTCTCAAGTGGCACAA
		GATAGCAGAGCCCATGCATTTTAATGGCTGAGACTGCTAAGAGTGAACCTAAACACTTACAAGTTGCA
		GAGAGAAATGAAAAAGTAATTACATGCTATTAGCATTGAGAAATGTTGACAAATTAATTTGTTGGGAA
		CCAAAGATAGCATTTCTGATGACAACTCCCACAGTGATTGGCCAGTTGTATGATGAGTACACTGCTGG
		AAAGAGGGTAAACTGGGAGTTAGTGGATGGTCCCAATGCCCTGCCTACAGCAGAGTGCCAACCAGCCC
		TGAGTGCAAAATTCAAGTTCAATGTGTGTGCTTGTGTGTGGTGTGCTTTATGGACCCGCAAATACCAT
		ATTCATTATTGATGATAAGATCTTCACAGAATCCTGTAGCTACTAATGCATTGAGTTTTTAATCTCAG
		TACATCAGCCAGGAGGAGCCAGATCACAGGGTAGTGATGTCTACTGGGATTATACTCATAACATCTAC
		ACAAAACAAGTTGAGAAGGATCCACGTTTTCATTGTTTATCAGAATTGTATCTCATTTGGCTGAGCAT
		TACTTTTGTCAGAATGTGTTATCTGTAAACCATGTGTAGTGAAATTCTTCTGTAACTTTGGATTAAAG
		GTATTTATGGTCTTTTTGTTTGTTTGATTTTTAAGTAAGTTATTTCTTTTGTAGACCTGCTGATGGTA
		TGGTTCCATCCTTCTGACCTCAGCATCCAATCTTTTTAAGGATTTTTGTTTTCAATATTGTTATTTTA
		AATTGTGGTTGAAGCAATAGAAAATTGAAATATGGATTGTGCATGACTGTGTCTTGAGTGTAAAAATA
		TTGCAGTTTGAAACTTGGACCTAAAGTATTGCAAATAAAAATGACAAACATCAATGA

7191	Human TRNP1	GGGGTGGGGGCTGTGGCCGTGTCTAGCTGTTCGGGTGTGCTGTGGTCATCCTCCCTGCGCACCTACAG
	mRNA	CCGCAGACCGCCGGTGGGGGGCGGGGGATGCCGGGCTGCCGCATCAGCGCCTGCGGCCCGGGGGCCCA
	NM_001013642.	GGAGGGGACGGCAGAGCAGAGGTCGCCGCCGCCGCCCTGGGATCCCATGCCGTCCTCTCAGCCCCCGC
	3	CCCCAACTCCGACCTTGACTCCTACCCCGACCCCGGGTCAGTCCCCGCCGCTGCCGGACGCAGCTGGG
	(GI:1519242294	GCTTCAGCAGGCGCGGCCGAGGACCAGGAGCTGCAGCGCTGGCGCCAGGGCGCTAGCGGGATCGCGGG
	version 3)	GCTCGCCGGCCCCGGAGGGGGCTCTGGCGCGGCTGCGGGGGCGGGGGGCCGCGCGCTGGAGCTGGCCG
		AAGCACGGCGGCGGCTGCTGGAGGTGGAGGGCCGCCGGCGCCTGGTGTCGGAGCTGGAGAGCCGCGTG
		CTGCAGCTGCACCGCGTTTTCTTGGCGGCCGAGCTGCGCCTGGCGCACCGCGCGGAGAGCCTGAGCCG
		CCTGAGCGGCGGCGTGGCGCAGGCCGAGCTCTACCTGGCGGCTCACGGGTCGCGCCTCAAGAAGGGCC
		CGCGCCGCGGCCGCCGCGGCCGACCCCCCGCGCTGCTGGCCTCGGCGCTGGGCCTGGGCGGCTGCGTG
		CCCTGGGGTGCCGGGCGACTGCGGCGCGGCCACGGCCCCGAGCCCGACTCGCCCTTCCGCCGCAGCCC
		GCCCCGCGGCCCCGCCTCCCCGCAGCGCTGACCTCCACGCCCGGACCCCTGGCCACCCCGACAAGCTT
		CGCCGAGGTGCCGACCGACCGACTGATCGCGGACGCCGGCTGGAAGGACTACGGATCCGCAGGAAGAG
		GCAGTTGGGGGCCAGGGGCCCAGTAGAGGAGGCTGAGCTCCTTCCAACTCCTCAGAACCTCCACTCTA
		TGGATCTGGACCTCTGGATTCGGCTTTCTCCCTGGGCACTGCCTTCAGGAAGACGTTGAGAATTGACC
		TTACACAATCCCAGCGCCCTCCTCACAGGAGCCTTTCACTTTACAGTGGCAAGGGGCTGGTTCTGGAG
		AACTGGCTGATGCTCTGAATTTCTTCATATACCCCACATTTGACTTTGGCTTACACTGTACAATTGGA
		GATGTTGCTACAGGTCCCTGAGATGCAATCAGATTAAGCGTAGCAAGCATTGCCAATGGGAAAGTCAA
		AATAATTTATTTTTTTTCCCTTTCCCCCTACCCCATCCCCAGCCAAGAATTTCTTTTCAAGATATCGT
		CATCATTCTTAAACAACATTCTTAACCCCCAGCTGGGGTCCCCATTTTAATAGATGTCATTGCTTCAA
		GTCTAACGGCGCCGGGAGGCCTGTTTGAGGGAAAACATTAGTTTGAAAAATCCCCGTTCCCTTCATCC
		ACTGCCCTTGTTCTCCACGTGGGAGTGTGCTTGTGGCCCCTCAGAAAGATAGTCTGCTGGCTCCTAGG
		GGTTGGGGTGGGGGACACACCTTTTTCTCAGGAAGAGGTGATGGCAATGTAAAACATCTAAGCAAAGT
		TTTAAATGAAAAAAAGGAAACACATTTAAACATCCTGATAATGGAGGGAAGGGGGGCACATTTACACA
		TAGCCCAGAACTTGTAGAATTCTGCATAGTGAATGTATATTGAATTAGTCTCCTGCCTTATACATTCA
		GGAGGAATAAATTTCCATAATGTAAGGCAAATGCATGGGGTTCTGAGGTTCACTTTGCAAGTGCCCTT
		GCTGCCTTTCCTCTGTGTCTATTATGGCTCTTTAAGTTGACGGTTCCTGGAGCAGCTTGTATTTAGTT
		TCGTTTGGCAGTCTGGCCCTGTTGACTTTGATTTGCAGACCAATTCTCCCTTGACCTGACTCACAGCC
		GCCTGCTCTTACCCCCCTCCTCAGGAAGTCTTCCTCATTAAAGGATGTGATGACGGA

7192	Human APLN	GAGCATTCTCTCTGGCAGCCGGGGTCACGGGCAGTTGCAGCCGCGGCCGAGCAGCCAGCCGCTAAGAA
	mRNA	AGAGCTCGCCGCTGCCGCTCCCGGAGCCGCCGAGGCCAGCTTCGCGGCGCTGCCCCGCGGCGGGAGAG
	NM_017413.5	GAGGCTGCAGAAGAGCGGAGGCGGCCAGCGGGAGCGGCGGGGCTCAGCGCGCACACTCAGCGGCCGGG
	(GI:1519315208	GAGCCTCCCGAGCTCTGCGCCCGCACGCGCCAGCCGCGGCTCGCGCCTTTCTTGGCCTCCGGGCGCCC
	version 5)	GACCTCTCCTCCCCCGCGCCGGCTCGCCGGGGCCGCGGCGGCCCAAGGAGCAGCATGAATCTGCGGCT
		CTGCGTGCAGGCGCTCCTGCTGCTCTGGCTCTCCTTGACCGCGGTGTGTGGAGGGTCCCTGATGCCGC
		TTCCCGATGGGAATGGGCTGGAAGACGGCAATGTCCGCCACCTGGTGCAGCCCAGAGGGTCAAGGAAT
		GGGCCAGGGCCCTGGCAGGGAGGTCGGAGGAAATTCCGCCGCCAGCGGCCCCGCCTCTCCCATAAGGG
		ACCCATGCCTTTCTGAAGCAGGACTGAAGGGGCCCCCAAGTGCCCACCCCCGGCGGTTATGTCTCCTC
		CATAGATTGGTCTGCTTCTCTGGAGGCCTCACGTCCATTCAGCTCTCACCTCGCACCTGCTGTAGCCA
		CCAGTGGGCCCAGCTCTTCTCACCTGCCTGCTTCCCCCAGTGGCGTGCTCCTGGCTGTAGTTTGGATG
		ATTCCCGTTCTCTCACAAGAATCCGTCCAGTCCATCTTCCTGGCCCCTCCCTGGACTGACTTTGGAGA
		CCTAGCCCCAGAAAGCCTCCCTTCTTCTCCAGGTCCCCTCCGCCCTAGTCCCTGCCTGTCTCATCTAA
		CGCCCCAAACCTTCATTTGGGCCTTCCTTCCTCATGTCTGCCCTGAGCGCGGGGTGGAAGTGCTCCCT
		TCTGTGGGCTCCAGCAGATCCCTTGTTTTCCTGTCAGTTGGACCCCTCACCTGGCCTCCAGGGAAGAA
		TGCAGAGAAAAGCAAGGAGAGACTCTAGTTAAGAGGTGCTGGCTGCGGGGATCCAGACAGGGCACATT
		GGGGGCATGGAAGTGCCAGGGTGGTTTTCAGGAGCTCTGGTGAAGTGGGTGGAGCATCAGCGTTTGCT
		CAGTTAAGGGAGAGGTAGAGAGGGGCCCGTGAAGTCCTTTGTCACTTCTCTTGCCTTAGTGTGCCTCC
		CAATACTCCCTTCTTCCTGCCCCCACACCCCATCCCCAGCTAGCCCAAGCTCCAGGTCAGGAGGGGAG
		GGTGCTGGGCCTGACATGGCTATATACCCTCCCAGGAGTAAAAGCCAAGCAAGAGGTTGTTTTTGCCA
		AGAATCACAGAATGTTAGAGCTGACAGGACCCTTGAAGGTCACTTAGCCTTCTTAGGCAAACGCCTGC
		AAAACAGAAGCCTGGAGAGGGGAGTGACCTGCTCAGAGTCATTGCAGAGCCGGGATGGGGACCAGGTC
		TCCCATCTCCTACTTTATGACGCCCTCTTCCCTCTTGATGATGTCTTTTCAAAGCAAATGAAGTGCCT
		TTTCCCGAGGCTGGGGCTGGGGGTGGCTGGGAGGGGAAGGGAAGGGAGAGGCAAGCTGGCTGTGAACT
		GTCCTGTTGTGGGGCTGGAGCTGCTCCCACCTCCCTGACCTACCCCTGCTGCACCATTCCCCCAGCTG
		GGCTGGAAGGTTCCATAACTGGCCAGCTGCCCCCATAACTGGCAGCATTCCCAGACCCAGGGTACTCT
		AATAGGGGCGGCTCAGGCACTGAGACTACCGCTCAACCCCAGGGTGGTTTTCAGGAGTCCGAGGTAGC
		CTTCAATCACTGGACTCCATGGCCTTCCCTTCGTGTTGACCGGACCTTCCTTCCAGGGCTTTTCCTTT
		GGGGGAGGCGGAGAGGGGAGAAGAAGGAAGGGAAGGGCAGAAGGAAGGAGGGAAGAAAAGAAAGCAAA
		GGAACAGAAGGAAGGAAAGAAAGATGGGAGGAAGTGCAGCAGGAATAGCACCCTCTCCCCGGGAGGCC
		CTAGCTTCCGTGAGGGGCCATCACCAGCCATTCCTTGGAGGGGGCTTTCTCCCCTTTTGCTTGAGCAG
		GGTTCCCAGGAGGGAGAAAGAGAAGACAAGAGCCTGATGCCCAACTTTGTGTGTGTGGGGACGGGGGA
		GTCAGGGCCCCCCAAGTCCCACAATAGCCCCAATGTTTGCCTATCCACCTCCCCCAAGCCCCTTTACC
		TATGCTGCTGCTAACGCTGCTGCTGCTGCTGCTGCTGCTTAAAGGCTCATGCTTGGAGTGGGGACT
		GGTCGGTGCCCAGAAAGTCTCTTCTGCCACTGACGCCCCCATCAGGGATTGGGCCTTCTTTCCCCCTT
		CCTTTCTGTGTCTCCTGCCTCATCGGCCTGCCATGACCTGCAGCCAAGCCCAGCCCCGTGGGGAAGGG
		GAGAAAGTGGGGGATGGCTAAGAAAGCTGGGAGATAGGGAACAGAAGAGGGTAGTGGGTGGGCTAGGG
		GGGCTGCCTTATTTAAAGTGGTTGTTTATGATTCTTATACTAATTTATACAAAGATATTAAGGCCCTG
		TTCATTAAGAAATTGTTCCCTTCCCCTGTGTTCAATGTTTGTAAAGATTGTTCTGTGTAAATATGTCT
		TTATAATAAACAGTTAAAAGCTGACAGTTCGCCCTTACTCTTGGAGGTCATGTTCAGGAGGGGCATTC
		CTTTCCCCTGGGGGTCATGGGTGTCCCCATGCCCACATATTGCACGTGCAGGGAGGTAAGTGCCTGCA
		TCCCAAATCGGTTCTAGGTCAACTGGCCTCAAACTGATTTGCCATGAGCTCACAAAATGAATCCCTAT
		GCTTAATGACCAGGTCACATAAAATCCAGCCCACTTACAGGTTTTCTGGCATCTGTTTGGGTGTCCTA
		ATTTTTTTGGCAGTGTCATTTGAAGAATTTTTTTAAAGCAGTTTATTTAAGAACATACTGATTAAATG
		CAGGATCGCTACTAAAAATTGTTTTGTATCCTTGGTGGGTGTCTTCTGCTATTTTATCTACTTTTGAA
		CACTTTCAGGACTTTTTAGCCAGTTTGCCTTTCTTGAAAAATGTTATGTTTTCAGCAATAAATACATT
		TGATAATGACTTTGTTTGTATCATTTTATGTTTCACAAAGTAGAGTTGCTTGATGAATGAGATAGCCT
		GAAAAATAAAATGCAAAGAGTTCAATATAA

7193	Human KIF20A	GGAGTTGTGCTCTGCGGCTGCGAAAGTCCAGCTTCGGCGACTAGGTGTGAGTAAGCCAGTATCCCAGG
	transcript	AGGAGCAAGTGGCACGTCTTCGGACCTAGGCTGCCCCTGCCGTCATGTCGCAAGGGATCCTTTCTCCG
	variant	CCAGCGGGCTTGCTGTCCGATGACGATGTCGTAGTTTCTCCCATGTTTGAGTCCACAGCTGCAGATTT
	1 mRNA	GGGGTCTGTGGTACGCAAGAACCTGCTATCAGACTGCTCTGTCGTCTCTACCTCCCTAGAGGACAAGC
	NM_005733.3	AGCAGGTTCCATCTGAGGACAGTATGGAGAAGGTGAAAGTATACTTGAGGGTTAGGCCCTTGTTACCT
	(GI:1519313609	TCAGAGTTGGAACGACAGGAAGATCAGGGTTGTGTCCGTATTGAGAATGTGGAGACCCTTGTTCTACA
	version 3)	AGCACCCAAGGACTCTTTTGCCCTGAAGAGCAATGAACGGGGAATTGGCCAAGCCACACACAGGTTCA
		CCTTTTCCCAGATCTTTGGGCCAGAAGTGGGACAGGCATCCTTCTTCAACCTAACTGTGAAGGAGATG
		GTAAAGGATGTACTCAAAGGGCAGAACTGGCTCATCTATACATATGGAGTCACTAACTCAGGGAAAAC
		CCACACGATTCAAGGTACCATCAAGGATGGAGGGATTCTCCCCCGGTCCCTGGCGCTGATCTTCAATA
		GCCTCCAAGGCCAACTTCATCCAACACCTGATCTGAAGCCCTTGCTCTCCAATGAGGTAATCTGGCTA
		GACAGCAAGCAGATCCGACAGGAGGAAATGAAGAAGCTGTCCCTGCTAAATGGAGGCCTCCAAGAGGA
		GGAGCTGTCCACTTCCTTGAAGAGGAGTGTCTACATCGAAAGTCGGATAGGTACCAGCACCAGCTTCG
		ACAGTGGCATTGCTGGGCTCTCTTCTATCAGTCAGTGTACCAGCAGTAGCCAGCTGGATGAAACAAGT
		CATCGATGGGCACAGCCAGACACTGCCCCACTACCTGTCCCGGCAAACATTCGCTTCTCCATCTGGAT
		CTCATTCTTTGAGATCTACAACGAACTGCTTTATGACCTATTAGAACCGCCTAGCCAACAGCGCAAGA
		GGCAGACTTTGCGGCTATGCGAGGATCAAAATGGCAATCCCTATGTGAAAGATCTCAACTGGATTCAT
		GTGCAAGATGCTGAGGAGGCCTGGAAGCTCCTAAAAGTGGGTCGTAAGAACCAGAGCTTTGCCAGCAC
		CCACCTCAACCAGAACTCCAGCCGCAGTCACAGCATCTTCTCAATCAGGATCCTACACCTTCAGGGGG
		AAGGAGATATAGTCCCCAAGATCAGCGAGCTGTCACTCTGTGATCTGGCTGGCTCAGAGCGCTGCAAA
		GATCAGAAGAGTGGTGAACGGTTGAAGGAAGCAGGAAACATTAACACCTCTCTACACACCCTGGGCCG
		CTGTATTGCTGCCCTTCGTCAAAACCAGCAGAACCGGTCAAAGCAGAACCTGGTTCCCTTCCGTGACA
		GCAAGTTGACTCGAGTGTTCCAAGGTTTCTTCACAGGCCGAGGCCGTTCCTGCATGATTGTCAATGTG
		AATCCCTGTGCATCTACCTATGATGAAACTCTTCATGTGGCCAAGTTCTCAGCCATTGCTAGCCAGCT
		TGTGCATGCCCCACCTATGCAACTGGGATTCCCATCCCTGCACTCGTTCATCAAGGAACATAGTCTTC
		AGGTATCCCCCAGCTTAGAGAAAGGGGCTAAGGCAGACACAGGCCTTGATGATGATATTGAAAATGAA
		GCTGACATCTCCATGTATGGCAAAGAGGAGCTCCTACAAGTTGTGGAAGCCATGAAGACACTGCTTTT
		GAAGGAACGACAGGAAAAGCTACAGCTGGAGATGCATCTCCGAGATGAAATTTGCAATGAGATGGTAG
		AACAGATGCAACAGCGGGAACAGTGGTGCAGTGAACATTTGGACACCCAAAAGGAACTATTGGAGGAA
		ATGTATGAAGAAAAACTAAATATCCTCAAGGAGTCACTGACAAGTTTTTACCAAGAAGAGATTCAGGA
		GCGGGATGAAAAGATTGAAGAGCTAGAAGCTCTCTTGCAGGAAGCCAGACAACAGTCAGTGGCCCATC
		AGCAATCAGGGTCTGAATTGGCCCTACGGCGGTCACAAAGGTTGGCAGCTTCTGCCTCCACCCAGCAG
		CTTCAGGAGGTTAAAGCTAAATTACAGCAGTGCAAAGCAGAGCTAAACTCTACCACTGAAGAGTTGCA
		TAAGTATCAGAAAATGTTAGAACCACCACCCTCAGCCAAGCCCTTCACCATTGATGTGGACAAGAAGT
		TAGAAGAGGGCCAGAAGAATATAAGGCTGTTGCGGACAGAGCTTCAGAAACTTGGTGAGTCTCTCCAA
		TCAGCAGAGAGAGCTTGTTGCCACAGCACTGGGGCAGGAAAACTTCGTCAAGCCTTGACCACTTGTGA
		TGACATCTTAATCAAACAGGACCAGACTCTGGCTGAACTGCAGAACAACATGGTGCTAGTGAAACTGG
		ACCTTCGGAAGAAGGCAGCATGTATTGCTGAGCAGTATCATACTGTGTTGAAACTCCAAGGCCAGGTT
		TCTGCCAAAAAGCGCCTTGGTACCAACCAGGAAAATCAGCAACCAAACCAACAACCACCAGGGAAGAA
		ACCATTCCTTCGAAATTTACTTCCCCGAACACCAACCTGCCAAAGCTCAACAGACTGCAGCCCTTATG
		CCCGGATCCTACGCTCACGGCGTTCCCCTTTACTCAAATCTGGGCCTTTTGGCAAAAAGTACTAAGGC
		TGTGGGGAAAGAGAAGAGCAGTCATGGCCCTGAGGTGGGTCAGCTACTCTCCTGAAGAAATAGGTCTC
		TTTTATGCTTTACCATATATCAGGAATTATATCCAGGATGCAATACTCAGACACTAGCTTTTTTCTCA
		CTTTTGTATTATAACCACCTATGTAATCTCATGTTGTTGTTTTTTTTTATTTACTTATATGATTTCTA
		TGCACACAAAAACAGTTATATTAAAGATATTATTGTTCACATTTTTTATTGAATTCCAAATGTAGCAA
		AATCATTAAAACAAATTATAAAAGGGACAGAAAAA

7194	Human LTB	AGTCTCAATGGGGGCACTGGGGCTGGAGGGCAGGGGTGGGAGGCTCCAGGGGAGGGGTTCCCTCCTGC
	transcript	TAGCTGTGGCAGGAGCCACTTCTCTGGTGACCTTGTTGCTGGCGGTGCCTATCACTGTCCTGGCTGTG
	variant	CTGGCCTTAGTGCCCCAGGATCAGGGAGGACTGGTAACGGAGACGGCCGACCCCGGGGCACAGGCCCA
	1 mRNA	GCAAGGACTGGGGTTTCAGAAGCTGCCAGAGGAGGAGCCAGAAACAGATCTCAGCCCCGGGCTCCCAG
	NM_002341.2	CTGCCCACCTCATAGGCGCTCCGCTGAAGGGGCAGGGGCTAGGCTGGGAGACGACGAAGGAACAGGCG
	(GI:1720810086	TTTCTGACGAGCGGGACGCAGTTCTCGGACGCCGAGGGGCTGGCGCTCCCGCAGGACGGCCTCTATTA
	version 2)	CCTCTACTGTCTCGTCGGCTACCGGGGCCGGGCGCCCCCTGGCGGCGGGGACCCCCAGGGCCGCTCGG
		TCACGCTGCGCAGCTCTCTGTACCGGGCGGGGGGCGCCTACGGGCCGGGCACTCCCGAGCTGCTGCTC
		GAGGGCGCCGAGACGGTGACTCCAGTGCTGGACCCGGCCAGGAGACAAGGGTACGGGCCTCTCTGGTA
		CACGAGCGTGGGGTTCGGCGGCCTGGTGCAGCTCCGGAGGGGCGAGAGGGTGTACGTCAACATCAGTC
		ACCCCGATATGGTGGACTTCGCGAGAGGGAAGACCTTCTTTGGGGCCGTGATGGTGGGGTGAGGGAAT
		ATGAGTGCGTGGTGCGAGTGCGTGAATATTGGGGGCCCGGACGCCCAGGACCCCATGGCAGTGGGAAA
		AATGTAGGAGACTGTTTGGAAATTGATTTTGAACCTGATGAAAATAAAGAATGGAAAGCTTCAGTGCT
		GCCGATAAA

7195	Human LTB	CAGTCTCAATGGGGGCACTGGGGCTGGAGGGCAGGGGTGGGAGGCTCCAGGGGAGGGGTTCCCTCCTG
	transcript	CTAGCTGTGGCAGGAGCCACTTCTCTGGTGACCTTGTTGCTGGCGGTGCCTATCACTGTCCTGGCTGT
	variant	GCTGGCCTTAGTGCCCCAGGATCAGGGAGGACTGGGTTTCAGAAGCTGCCAGAGGAGGAGCCAGAAAC
	2 mRNA	AGATCTCAGCCCCGGGCTCCCAGCTGCCCACCTCATAGGCGCTCCGCTGAAGGGGCAGGGGCTAGGCT
	NM_009588.1	GGGAGACGACGAAGGAACAGGCGTTTCTGACGAGCGGGACGCAGTTCTCGGACGCCGAGGGGCTGGCG
	(GI:6996015,	CTCCCGCAGGACGGCCTCTATTACCTCTACTGTCTCGTCGGCTACCGGGGCCGGGCGCCCCCTGGCGG
	version 1)	CGGGGACCCCCAGGGCCGCTCGGTCACGCTGCGCAGCTCTCTGTACCGGGCGGGGGGCGCCTACGGGC
		CGGGCACTCCCGAGCTGCTGCTCGAGGGCGCCGAGACGGTGACTCCAGTGCTGGACCCGGCCAGGAGA
		CAAGGGTACGGGCCTCTCTGGTACACGAGCGTGGGGTTCGGCGGCCTGGTGCAGCTCCGGAGGGGCGA
		GAGGGTGTACGTCAACATCAGTCACCCCGATATGGTGGACTTCGCGAGAGGGAAGACCTTCTTTGGGG
		CCGTGATGGTGGGGTGAGGGAATATGAGTGCGTGGTGCGAGTGCGTGAATATTGGGGGCCCGGACGCC
		CAGGACCCCATGGCAGTGGGAAAAATGTAGGAGACTGTTTGGAAATTGATTTTGAACCTGATGAAAAT
		AAAGAATGGAAAGCTTCAGTGCTGCCGATAAA

Claims

What is claimed is:

1. A method of treating fibrosis in a disease characterised by fibrosis, comprising administering a therapeutically-effective amount of an inhibitory nucleic acid comprising or encoding antisense nucleic acid for inhibiting ITFG1 gene expression to a subject having the disease characterised by fibrosis.

2. The method according to claim 1, wherein the disease characterised by fibrosis is a disease characterised by fibrosis of the liver.

3. The method according to claim 2, wherein the disease characterised by fibrosis of the liver is selected from: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, mild liver fibrosis, advanced liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (ALFD), alcohol-related liver disease (ARLD), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), hepatitis, liver damage, liver injury, liver failure, metabolic syndrome, obesity, diabetes mellitus, end-stage liver disease, inflammation of the liver, lobular inflammation, and hepatocellular carcinoma (HCC).

4. The method according to claim 3, wherein the disease characterised by fibrosis of the liver is selected from: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC) hepatitis and liver damage.

5. The method according to claim 1, wherein the inhibitory nucleic acid is an siRNA, dsiRNA, shRNA or antisense oligonucleotide.

6. The method according to claim 1, wherein the inhibitory nucleic acid comprises one or more modified nucleotides selected from: 2′-O-methyluridine-3′-phosphate, 2′-O-methyladenosine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methyluridine-3′-phosphorothioate, 2′-O-methyladenosine-3′-phosphorothioate, 2′-O-methylguanosine-3′-phosphorothioate, 2′-O-methylcytidine-3′-phosphorothioate, 2′-fluorouridine-3′-phosphate, 2′-fluoroadenosine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluorocytidine-3′-phosphorothioate, 2′-fluoroguanosine-3′-phosphorothioate, 2′-fluoroadenosine-3′-phosphorothioate, and 2′-fluorouridine-3′-phosphorothioate.

7. The method according to claim 1, wherein the antisense nucleic acid for inhibiting the expression of ITFG1 comprises or consists of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs:457 to 1482.

8. The method according to claim 1, wherein the inhibitory nucleic acid comprises a moiety facilitating delivery to and/or uptake by a hepatocyte and/or hepatic tissue.

9. The method according to claim 1, wherein the inhibitory nucleic acid comprises one or more GalNAc moieties.

10. A method of inhibiting fibrosis of the liver in a subject, comprising administering to a subject in need thereof an inhibitory nucleic acid comprising or encoding antisense nucleic acid for inhibiting ITFG1 gene expression.

11. The method according to claim 10, wherein the subject has a disease characterised by fibrosis of the liver.

12. The method according to claim 11, wherein the disease characterised by fibrosis of the liver is selected from: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, mild liver fibrosis, advanced liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (ALFD), alcohol-related liver disease (ARLD), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), hepatitis, liver damage, liver injury, liver failure, metabolic syndrome, obesity, diabetes mellitus, end-stage liver disease, inflammation of the liver, lobular inflammation, and hepatocellular carcinoma (HCC).

13. The method according to claim 12, wherein the disease characterised by fibrosis of the liver is selected from: acute liver disease, chronic liver disease, metabolic liver disease, steatosis, liver fibrosis, primary sclerosing cholangitis (PSC), cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC) hepatitis and liver damage.

14. The method according to claim 10, wherein the inhibitory nucleic acid is an siRNA, dsiRNA, shRNA or antisense oligonucleotide.

15. The method according to claim 10, wherein the inhibitory nucleic acid comprises one or more modified nucleotides selected from: 2′-O-methyluridine-3′-phosphate, 2′-O-methyladenosine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methyluridine-3′-phosphorothioate, 2′-O-methyladenosine-3′-phosphorothioate, 2′-O-methylguanosine-3′-phosphorothioate, 2′-O-methylcytidine-3′-phosphorothioate, 2′-fluorouridine-3′-phosphate, 2′-fluoroadenosine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluorocytidine-3′-phosphorothioate, 2′-fluoroguanosine-3′-phosphorothioate, 2′-fluoroadenosine-3′-phosphorothioate, and 2′-fluorouridine-3′-phosphorothioate.

16. The method according to claim 10, wherein the antisense nucleic acid for inhibiting the expression of ITFG1 comprises or consists of a nucleotide sequence having at least 75% sequence identity to any one of SEQ ID NOs:457 to 1482.

17. The method according to claim 10, wherein the inhibitory nucleic acid comprises a moiety facilitating delivery to and/or uptake by a hepatocyte and/or hepatic tissue.

18. The method according to claim 10, wherein the inhibitory nucleic acid comprises one or more GalNAc moieties.