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WO2020101880A1 - Compositions et procédés pour le traitement du lupus érythémateux dissémine - Google Patents

Compositions et procédés pour le traitement du lupus érythémateux dissémine Download PDF

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Publication number
WO2020101880A1
WO2020101880A1 PCT/US2019/058492 US2019058492W WO2020101880A1 WO 2020101880 A1 WO2020101880 A1 WO 2020101880A1 US 2019058492 W US2019058492 W US 2019058492W WO 2020101880 A1 WO2020101880 A1 WO 2020101880A1
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Prior art keywords
agent
nucleic acids
rasgrp3
dna
binding
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PCT/US2019/058492
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English (en)
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Swapan NATH
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Oklahoma Medical Research Foundation
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Oklahoma Medical Research Foundation
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/154—Methylation markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/104—Lupus erythematosus [SLE]

Definitions

  • SLE Systemic lupus erythematosus
  • GWAS genome-wide association studies
  • the agent is 5-fluorouracil, olararib, meaparib, niraparib, talazoparib, veliparib, CEP 7922, E7016, ICG-001, C646, E1A, MI-3, or GSKI26.
  • the epigenetic locus is at least one of rs7170151, rsl l631591-rs7173565, rs9920715, rsl3385731, or rsl3725999.
  • the agent is delivered into a target cell via liposome, viral expression vector, CRISPR, particle(s), exosome(s), microvesicle(s), Zinc -finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), or a gene-gun.
  • the agent is a peptide that blocks the DNA portion of the DNA binding protein specific for the epigenetic locus.
  • the agent has a sequence selected from: 1 to 58.
  • the agent is a small molecule inhibitor of RASGRPl or RASGRP3, or reduces the transcription of RASGRPl or RASGRP3.
  • the agent blocks or reduces the binding of at least one of: lmRNP-K, H3K27AC, H3K4Mel, H3K4Me3, P300, PARP1, or IRF1 to DNA.
  • FIGS. 6A and 6B show Luciferase reporter assay for rs7170151, rsl l631591-rs7173565 and rs9920715 in 6A.
  • Jurkat and 6B HEK293 cells.
  • Empty vector pGL4.26 was used as reference.
  • NR non-risk.
  • P-values are for Student’s t-test.
  • FIGS. 19A to 19G show the effect of the risk genotypes on (FIG. 19A) RASGRP3 mRNA expression from LFRR cell line (FIG. 19B) Coriell cell lines (FIG. 19C) combined LFRR and Coriell cell line (999 FIG. 19D, 3020 Analysis FIG. 19E).
  • FIG. 19E mRNA expression of RASGRP3 against SNP rsl2613020
  • FIG. 19F mRNA expression of RASGRP3 against SNP rsl3425999.
  • the present inventions also determined the additional SLE association with RASGRP3 (RAS Guanyl Releasing Protein 3) as one of the most consistently replicated SLE signals.
  • RASGRP3 RAS Guanyl Releasing Protein 3
  • the inventors recently reported that multiple intronic variants explained RASGRP3-SLE association in Asians. The inventors hypothesized that these intronic variants influence RASGRP3 expression by modulating epigenetic regulation, which could be associated with SLE risk.
  • Pairs of primers designed to selectively hybridize to nucleic acids corresponding to selected genes are contacted with the template nucleic acid under conditions that permit selective hybridization.
  • high stringency hybridization conditions may be selected that will only allow hybridization to sequences that are completely complementary to the primers.
  • hybridization may occur under reduced stringency to allow for amplification of nucleic acids containing one or more mismatches with the primer sequences.
  • the template-primer complex is contacted with one or more enzymes that facilitate template-dependent nucleic acid synthesis. Multiple rounds of amplification, also referred to as "cycles,” are conducted until a sufficient amount of amplification product is produced.
  • the probe molecules on the surface of the substrates will correspond to selected genes being analyzed and be positioned on the array at a known location so that positive hybridization events may be correlated to expression of a particular gene in the physiological source from which the target nucleic acid sample is derived.
  • the substrates with which the probe molecules are stably associated may be fabricated from a variety of materials, including plastics, ceramics, metals, gels, membranes, glasses, and the like.
  • the arrays may be produced according to any convenient methodology, such as preforming the probes and then stably associating them with the surface of the support or growing the probes directly on the support. A number of different array configurations and methods for their production are known to those of skill in the art and disclosed in U.S. Pat. Nos.
  • SNP prioritization The inventors used a prioritization algorithm to narrow down the large list of SNPs for further validation.
  • the strategy consisted of two Bayesian algorithms to score each SNP (3dSNP (30) and RegulomeDB (31)), as well as additional expression, epigenetic, and preferential allele-specific information about each SNP.
  • 3dSNP (30) tool to assign functional weights based on the presence of enhancers, promoters, experimentally determined (ChIP-seq) transcription factor binding sites (TFBSs), TFBS motif matching, evolutionary conservation, and presence of 3D chromatin interactions.
  • Luciferase reporter assays To test candidate SNP-containing regions for allele-specific enhancer activity; the inventors cloned all three SNPs (rsl l63159, rs7173565-rs7173565, and rs9920715) individually into the enhancer reporter plasmid 4.26 (Promega USA). In brief, genomic DNA from the Coriell cell line (obtained from NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research) was amplified using specific primers containing Kpnl and Hindlll sites.
  • the inventors then examined the 18 GWS SNPs with bioinformatic and epigenomic analysis (Table 2).
  • the inventors’ top SNP (rs8032939) was previously reported as a rheumatoid arthritis (RA)-associated SNP (51).
  • RA rheumatoid arthritis
  • cytokine production A critical feature in SLE pathogenicity is cytokine production (54) ; thus, the inventors investigated if these SNPs alter cytokine abundance.
  • the candidate SNPs significantly increased expression of interleukins IL6 and IL22 and tumor necrosis factor (TNFa), while SNP rs9920715 exclusively increased IL22 expression. Allele-specific binding.
  • the inventors found that 14 of the candidate GWS SNPs also had allele-specific binding (ASB) to H2K27ac in monocytes, neutrophils, and T-cells, while rs9920715 showed ASB with H3K4Mel in T-cells and neutrophils.
  • ASB allele-specific binding
  • the inventors fine-mapped their previously reported SLE locus near RAS guanyl- releasing protein 1 (RASGRP1), a lynchpin of T-cell development and the RAS/MAP kinase signaling cascade following antigen exposure.
  • the inventors performed a trans-ethnic meta-analysis of the locus with cohorts of Asian and European descent, followed by multiple lines of bioinformatic analyses of its epigenetic context to prioritize SNPs as candidate causal variants.
  • Experimental testing of the top candidates validated them as plausible variants underlying association of this locus with SLE (and perhaps other autoimmune phenotypes).
  • the inventors identified two independently associated regions correlated with RASGRP1 regulation and expression.
  • the first signal lies in RASGRP1 intron 2, represented by SNPs rsl l631591-rs7173565 and rs7170151, which regulate RASGRP1 expression as eQTLs (esophageal mucosa and skin), enhancers (in CD8 + T-cells, and thymic and lymphoblastoid cell lines), and as interaction anchors with the nearby C15orf53 promoter.
  • Abnormal expression of RASGRP1 isoforms play important roles in lymphocytes of SLE patients regardless of their clinical disease activity, and may contribute to impaired lymphocyte function and increased apoptosis in SLE patients (14).
  • Abnormal RASGRP1 expression also induces ERK and JNK phosphorylation in the MAPK pathway, which in turn alters T-cell development, contributes to long-term organ damage and ultimately increases SLE susceptibility (19, 75, 76).
  • the inventors also observed the role of RASGRP1 expression in the phosphorylation of ERK activity. Altogether, these results indicate increased RASGRP1 expression correlated with the risk alleles in these functional SLE loci and T-cell dysfunction.
  • this study did not examine the differences in RASGRP1 isoform expression reportedly associated with SLE and correlated with low RASGRP1 expression (14).
  • the inventors used in-silico bioinformatics to define the potential regulatory effects of three candidate variants on gene expression using data from ENCODE, ROADMAP and GTEx databases.
  • the inventors used a combination of DNA pulldown, Electrophoretic Mobility Shift Assay (EMSA), Super-shift, Western blot, Mass Spectrometry and ChIP-qPCR to identify allele-specific DNA- bound proteins and differential histone marks.
  • the inventors measured the RASGRP3 mRNA and protein expressions and also studied the enhancer/promoter activity of these variants. Bioinformatics predicted that these variants are located in active chromatin and have the potential to be dual enhancers/promoters.
  • RASGRP3 also showed to induce Ras-MAPK activation via DAG and by phosphorylation by PKC in B-cells in melanoma [28] But there is far less information known about the potential role of RASGRP3 in B-cells for lupus pathogenesis. Bioinformatics and epigenetic analysis. In silico prediction of epigenetic regulation.
  • RASGRP3 protein expression EBV-transformed B cells were harvested and lysed in Whole Cell Extraction Buffer (25mM Tris, 1% Triton X-100, 150mM NaCl, ImM EDTA and protease inhibitors). Protein concentration in each cell line was measured using Quick Start Bradford Protein Assay Kits and adjusted to a final protein concentration of 2mg/mL.
  • RASGRP3 protein was detected on western blot using the antibody against RASGRP3 (Cell Signaling (C33A3), Beverly, MA, USA).
  • Anti-beta actin antibodies were purchased from Cell Signaling Technology, Inc. and were used to detect protein expression of beta actin. Densitometry analysis of immunore active bands was performed using National Institutes of Health Image J (National Institutes of Health) applied to digital images of respective Western blots.
  • DNA binding protein complexes were detected by electrophoretic mobility shift assay (EMSA) and DNA pull down assay using a 41 base long dsDNA containing the candidate alleles.
  • Nuclear extract was prepared from Jurkat (T-cells) and Toledo cell (B- cells) lines and further mixed with biotin labeled dsDNA (risk vs non-risk) bound to magnetic beads containing streptavidin.
  • EMSA showed multiple bands of DNA bound proteins (FIG. 17A).
  • the inventors observed differences in binding between the DNA/Protein complexes of risk and non-risk genotypes of SNP rs 13385731. The molecular weight of this complex was lOOkDa.
  • words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skill in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention concerne des compositions et des procédés pour le traitement du lupus érythémateux disséminé (LED) consistant à identifier un sujet ayant besoin d'un traitement pour le LED; et à fournir au sujet une quantité efficace d'un agent bloquant la liaison d'une protéine de liaison à l'ADN à une mutation dans un locus épigénétique qui affecte la transcription de RASGRP1 ou RASGRP3.
PCT/US2019/058492 2018-11-14 2019-10-29 Compositions et procédés pour le traitement du lupus érythémateux dissémine Ceased WO2020101880A1 (fr)

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US62/767,354 2018-11-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116064781A (zh) * 2023-01-16 2023-05-05 温州医科大学 一种5-羟甲基胞嘧啶的用途
CN119432926A (zh) * 2024-11-18 2025-02-14 首都医科大学附属北京儿童医院 一种系统性红斑狼疮小鼠模型的构建方法及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094636A1 (fr) * 2003-04-24 2004-11-04 Galapagos Genomics N.V. Constructions demontables effectives d'arnsi
US20090221686A1 (en) * 2000-10-06 2009-09-03 Marcus Hecker Modulation of the Transcription of Pro-Inflammatory Gene Products
US20120100160A1 (en) * 2008-11-26 2012-04-26 Immune Disease Institute Methods for Inducing Mixed Chimerism
US20180042938A1 (en) * 2012-04-06 2018-02-15 Indus Pharmaceuticals, Inc. Novel compositions of combinations of non-covalent dna binding agents and anti-cancer and/or anti-inflammatory agents and their use in disease treatment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090221686A1 (en) * 2000-10-06 2009-09-03 Marcus Hecker Modulation of the Transcription of Pro-Inflammatory Gene Products
WO2004094636A1 (fr) * 2003-04-24 2004-11-04 Galapagos Genomics N.V. Constructions demontables effectives d'arnsi
US20120100160A1 (en) * 2008-11-26 2012-04-26 Immune Disease Institute Methods for Inducing Mixed Chimerism
US20180042938A1 (en) * 2012-04-06 2018-02-15 Indus Pharmaceuticals, Inc. Novel compositions of combinations of non-covalent dna binding agents and anti-cancer and/or anti-inflammatory agents and their use in disease treatment

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XU-JIE ZHOU ET AL: "Novel identified associations of RGS1 and RASGRP1 variants in IgA Nephropathy", SCIENTIFIC REPORTS, vol. 6, no. 1, 35781, 2 November 2016 (2016-11-02), pages 1 - 7, XP055709422, ISSN: 2045-2322, DOI: 10.1038/srep35781 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116064781A (zh) * 2023-01-16 2023-05-05 温州医科大学 一种5-羟甲基胞嘧啶的用途
CN119432926A (zh) * 2024-11-18 2025-02-14 首都医科大学附属北京儿童医院 一种系统性红斑狼疮小鼠模型的构建方法及其应用
CN119432926B (zh) * 2024-11-18 2025-08-26 首都医科大学附属北京儿童医院 一种系统性红斑狼疮小鼠模型的构建方法及其应用

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