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NZ735289B2 - VARIANT RNAi - Google Patents

VARIANT RNAi Download PDF

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Publication number
NZ735289B2
NZ735289B2 NZ735289A NZ73528916A NZ735289B2 NZ 735289 B2 NZ735289 B2 NZ 735289B2 NZ 735289 A NZ735289 A NZ 735289A NZ 73528916 A NZ73528916 A NZ 73528916A NZ 735289 B2 NZ735289 B2 NZ 735289B2
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New Zealand
Prior art keywords
rnai
vector
promoter
optionally
sequence
Prior art date
Application number
NZ735289A
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NZ735289A (en
Inventor
Riordan Catherine O
Adam Palermo
Brenda Richards
Sergio Pablo Sardi
Antonius Song
Lisa M Stanek
Original Assignee
Genzyme Corporation
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Publication date
Application filed by Genzyme Corporation filed Critical Genzyme Corporation
Priority to NZ772770A priority Critical patent/NZ772770B2/en
Priority claimed from PCT/US2016/017207 external-priority patent/WO2016130589A2/en
Publication of NZ735289A publication Critical patent/NZ735289A/en
Publication of NZ735289B2 publication Critical patent/NZ735289B2/en

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    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/53—Physical structure partially self-complementary or closed
    • C12N2310/533—Physical structure partially self-complementary or closed having a mismatch or nick in at least one of the strands
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    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
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    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
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    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector

Abstract

Provided herein are RNAi molecules including a first strand containing a guide sequence and a second strand comprising a non-guide sequence where the non-guide sequence contains a bulge opposite the seed region of the guide sequences; e.g., opposite the cleavage sequence. In some aspects, the invention provides RNAi for treating Huntington's disease. Further provided herein are expression cassettes, vectors (e.g., rAAV, recombinant adenoviral, recombinant lentiviral, and recombinant HSV vectors), cells, viral particles, and pharmaceutical compositions containing the RNAi. Yet further provided herein are methods and kits related to the use of the RNAi, for example, to treat Huntington' s disease.

Claims (20)

1. An RNAi comprising a first strand and a second , wherein a) the first strand and the second strand form a ; b) the first strand comprises a guide region of at least 19 bases, wherein the guide region comprises a seed region comprising bases 1-N of the guide region, wherein N=7 or N=8; and c) the second strand comprises a non-guide region of at least 19 bases, wherein the non-guide region ses a bulge sequence opposite of base 1 of the guide region, wherein the bulge is an asymmetrical internal loop formed by one or more bases of the non-guide region in the duplex that lack a complementary base on the guide region, wherein the bulge is flanked by bases that do basepair with the guide region, and wherein the bulge is opposite the 3’ cleavage site of the mature guide region.
2. The RNAi of claim 1, wherein: (a) the bulge comprises 1 to 10 nucleotides, wherein ally the bulge comprises 1- 3 nucleotides; and/or (b) RNAi comprises a second bulge, wherein the second bulge is located on the first strand in the guide region located 3’ to the seed region.
3. The RNAi of any one of claims 1-2, wherein: (a) the duplex is between 19 and 25 or between 19 and 23 base pairs in length; (b) the first and/or second strand further comprises a 3' ng region, a 5' overhang region, or both 3' and 5' overhang regions; and/or (c) the first strand and the second strand are linked by means of RNA linker e of forming a loop structure, n optionally: (i) the RNA linker comprises 4 to 50 nucleotides; (ii) the loop structure comprises 4 to 20 nucleotides; and/or (iii) the RNAi comprises 5’ to 3’ the second strand, the RNA linker, and the first strand; or the RNAi comprises 5’ to 3’ the first strand, the RNA linker, and the second .
4. The RNAi of any one of claims 1-3, wherein: (a) the sequence comprises one or more CpG motifs; and/or (b) the sequence comprises one or more CpG motifs in the seed region.
5. The RNAi of any one of claims 1-4, wherein the RNAi comprises the nucleotide sequence about 90% identical to the nucleotide sequence of SEQ ID NO:3, wherein ally the RNAi comprises the nucleotide sequence of SEQ ID NO:3.
6. The RNAi of any one of claims 1-5, the RNAi is a small inhibitory RNA (siRNA), a microRNA (miRNA), or a small hairpin RNA (shRNA).
7. The RNAi of any one of claims 1-6, wherein the RNAi targets RNA ng a ptide associated with a disorder, wherein optionally: (a) the er is a CNS er; (b) the disorder is lysosomal storage disease (LSD), gton's disease, epilepsy, Parkinson's e, Alzheimer's disease, stroke, corticobasal degeneration (CBD), corticobasal ganglionic degeneration (CBGD), frontotemporal dementia (FTD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) or cancer of the brain; and/or (c) the disorder is Huntington’s e.
8. The RNAi of claim 7, wherein the polypeptide is huntingtin, and wherein ally: (a) the huntingtin comprises a mutation associated with Huntington’s disease; and/or (b) the guide region comprises the sequence 5’-UAGACAAUGAUUCACACGGU-3’ (SEQ ID NO:1) and the non-guide region comprises the sequence 5’- ACCGUGUGUCAUUGUCUAA-3’ (SEQ ID NO:2); or (c) the guide region comprises the sequence 5’-UCGACAAUGAUUCACACGGU-3’ (SEQ ID NO:15) and the non-guide region comprises the sequence 5’- ACCGUGUGUCAUUGUCGAA-3’ (SEQ ID NO:16); or (d) the guide region comprises the sequence 5’-UAGACGAUGAUUCACACGGU-3’ (SEQ ID NO:17) and the non-guide region comprises the sequence 5’- ACCGUGUGUCAUCGUCUAA-3’ (SEQ ID NO:18).
9. A method to reduce the toxicity of a RNAi comprising introducing a bulge in the de region of the RNAi to generate a RNAi of any one of claims 1-8.
10. An expression construct comprising nucleic acid encoding the RNAi of any one of claims 1-8, wherein optionally the nucleic acid encoding the RNAi comprises a miRNA ld, wherein optionally the nucleic acid ng the RNAi comprises a miR-155 scaffold.
11. The expression uct of claim 10, wherein the nucleic acid encoding the RNAi is operably linked to a promoter, wherein optionally: (a) the promoter is capable of expressing the RNAi in the brain of a mammal; and/or (b) the promoter is selected from a cytomegalovirus (CMV) immediate early promoter, an RSV LTR, a MoMLV LTR, a phosphoglycerate kinase- 1 (PGK) promoter, a simian virus 40 (SV40) promoter, a CK6 promoter, a transthyretin er (TTR), a TK promoter, a tetracycline responsive promoter (TRE), an HBV promoter, an hAAT er, a LSP promoter, a chimeric liver-specific promoter (LSP), an E2F promoter, a telomerase (hTERT) promoter; a cytomegalovirus enhancer/chicken beta-actin/Rabbit ß-globin promoter (CAG) promoter, an elongation factor 1-alpha promoter (EFl-alpha) promoter, a human ß-glucuronidase er, a chicken ß-actin (CBA) promoter, a iral Rous sarcoma virus (RSV) LTR promoter, a dihydrofolate reductase promoter, and a ß-actin er.
12. The expression construct of claim 10 or 11, wherein the expression construct further comprises a polyadenylation signal, wherein optionally the polyadenylation signal is a bovine growth hormone polyadenylation signal, an SV40 enylation signal, or a HSV TK pA.
13. A vector comprising the expression construct of any one of claims 10-12, wherein optionally: (a) the vector is a recombinant adeno-associated virus (rAAV) vector; (b) the vector is a recombinant adenoviral vector, wherein optionally the recombinant adenoviral vector is derived from Adenovirus pe 2, 1, 5, 6, 19, 3, 11, 7, 14, 16, 21, 12, 18, 31, 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24-30, 37, 40, 41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, , AdHu50, AdC6, AdC7, AdC69, bovine Ad type 3, canine Ad type 2, ovine Ad, or porcine Ad type 3; (c) the vector is a recombinant lentiviral vector, wherein optionally the recombinant lentiviral vector is derived from a lentivirus pseudotyped with lar stomatitis virus (VSV), lymphocytic choriomeningitis virus (LCMV), Ross river virus (RRV), Ebola virus, Marburg virus, Mokala virus, Rabies virus, RD114 or variants therein; (d) the vector is a rHSV vector, wherein optionally the rHSV vector is derived from rHSV-1 or rHSV-2.
14. The vector of claim 13, wherein the vector is a rAAV vector, and wherein the expression construct is flanked by one or more AAV inverted terminal repeat (ITR) sequences, wherein optionally: (a) the expression construct is flanked by two AAV ITRs; and/or (b) the AAV ITRs are AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrh10, AAV11, AAV12, AAV2R471A, AAV DJ, a goat AAV, bovine AAV, or mouse AAV serotype ITRs, wherein optionally the AAV ITRs are AAV2 ITRs.
15. The vector of claim 14, wherein the rAAV vector comprise 5’ to 3’ an AAV2 ITR, a promoter, nucleic acid ng the RNAi, a polyadenylation signal, and an AAV2 ITR; and wherein optionally: (a) the promoter is a CBA promoter; (b) the polyadenylation signal is a bovine growth hormone enylation signal; and/or (c) the rAAV vector comprises 5’ to 3’ an AAV2 ITR, the CBA promoter, nucleic acid encoding the RNAi, a bovine growth hormone enylation signal, and an AAV2
16. The vector of claim 14 or 15, wherein the vector r comprises a stuffer nucleic acid, wherein optionally: (a) the r nucleic acid is located between the promoter and the nucleic acid encoding the RNAi; and/or (b) the stuffer c acid comprises c acid ng a green fluorescent n (GFP), a human alphaantitrypsin (AAT) stuffer sequence, or a C16 P1 chromosome 16 P1 clone (human C16) stuffer sequence.
17. The vector of any one of claims 14-16, wherein the vector is a self-complementary rAAV vector, wherein optionally the vector comprises first nucleic acid sequence encoding the RNAi and a second nucleic acid sequence encoding a complement of the RNAi, wherein the first nucleic acid sequence can form intrastrand base pairs with the second nucleic acid sequence along most or all of its length; and wherein optionally the first nucleic acid sequence and the second nucleic acid sequence are linked by a mutated AAV ITR, wherein the mutated AAV ITR comprises a deletion of the D region and comprises a mutation of the terminal resolution sequence.
18. An isolated or non-human host cell comprising the vector of any one of claims 13-17, n optionally the cell is a central nervous system (CNS) cell.
19. A viral particle comprising the vector of claim 13, wherein: (a) the viral particle is an AAV particle encapsidating the rAAV vector; (b) the viral particle is an adenovirus particle encapsidating the inant adenoviral vector, wherein optionally the adenovirus particle comprises a capsid from Adenovirus serotype 2, 1, 5, 6, 19, 3, 11, 7, 14, 16, 21, 12, 18, 31, 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24-30, 37, 40, 41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, , AdHu36, AdHu37, , AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, bovine Ad type 3, canine Ad type 2, ovine Ad, or porcine Ad type 3, or a variant of an adenovirus serotype 5 capsid; (c) the viral particle is a lentiviral le encapsidating the inant lentiviral vector, wherein optionally the lentiviral particle comprises a capsid pseudotyped with vesicular stomatitis virus (VSV), lymphocytic choriomeningitis virus (LCMV), Ross river virus (RRV), Ebola virus, g virus, Mokala virus, Rabies virus, RD114 or variants therein; or (d) the viral particle is a HSV particle, wherein optionally the HSV particle is a rHSV- 1 particle or a rHSV-2 particle.
20. A recombinant AAV (rAAV) le comprising the vector of any one of claims 14- 17, n optionally the AAV viral particle comprises an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAVrh8R, AAV9, AAV10, AAVrh10, AAV11, AAV12, 71A, AAV
NZ735289A 2016-02-09 VARIANT RNAi NZ735289B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ772770A NZ772770B2 (en) 2016-02-09 Variant RNAi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562114578P 2015-02-10 2015-02-10
PCT/US2016/017207 WO2016130589A2 (en) 2015-02-10 2016-02-09 VARIANT RNAi

Publications (2)

Publication Number Publication Date
NZ735289A NZ735289A (en) 2024-07-26
NZ735289B2 true NZ735289B2 (en) 2024-10-30

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