Clinical epigenetic diagnostic for spermatogenic failure and future health risks

生精失败和未来健康风险的临床表观遗传学诊断

• 批准号: 10459080
• 负责人: Kristin R Brogaard
• 金额: $ 25.52万
• 依托单位: INHERENT BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459080
• 关键词: Abnormal DNA Repair; Accounting; Assisted Reproductive Technology; Biological Assay; Biological Sciences; Clinical; Collaborations; DNA; DNA Double Strand Break; DNA Repair; DNA Repair Gene; Defect; Development; Diagnosis; Diagnostic; Diagnostic tests; Epigenetic Process; Etiology; Exhibits; FANCB; Failure; Functional disorder; Future; Gametogenesis; Gene Family; General Population; Genes; Genetic; Genomic Instability; Goals; Guidelines; Health; Hypermethylation; Immune System Diseases; Impairment; Infertility; Klinefelter' s Syndrome; Knowledge; LIG4 gene; Laboratories; Leukocytes; MGMT gene; MLH1 gene; MSH3 gene; MSH6 gene; Male Infertility; Malignant Neoplasms; Medicine; Meiosis; Methylation; Microsatellite Repeats; Mismatch Repair; Modification; Mutation; Oligospermia; PMS2 gene; Pathway interactions; Patients; Phase; Production; Reproductive Medicine; Risk; Robertsonian Translocation; Sampling; Site; Small Business Innovation Research Grant; Source; Spermatogenesis; Syndrome; Testing; Urology; Vasovasostomy; Work; Y chromosome microdeletions; base; case control; circulating DNA; commercialization; cost effective; gene repair; genetic testing; human male; improved; male; member; men; novel; repaired; research study; sperm cell; standard of care; targeted sequencing; tool

SUMMARY / ABSTRACT – Inherent Biosciences Dr. Dolores Lamb from the Weill Cornell Medicine (WCM) has discovered a novel epi- genetic source of male-infertility that has been shown to be the most common genetic source of sperm impairment in men suffering for non-obstructive azoospermia (NOA). Inherent Biosciences in collaboration with WCM proposes the development of a cost-effective commercial diagnostic for use in genetic testing of incoming patients at the Department of Urology at WCM. Prior to this discovery, Klinefelter’s syndrome and Y chromosome microdeletions were the two most prevalent genetic causes of male infertility. Klinefelter’s syndrome and Y chromosome microdeletions account for 11% and 8% respectively in azoospermic men. According to the current AUA/ ASRM Guidelines, genetic testing for both Klinefelter’s syndrome and Y-chromosome microdeletion is recommended for all men with severe oligospermia or azoospermia to clarify etiology of male infertility prior to treatment (market size of 12.2 million men worldwide). Work from the Lamb Lab over the last 20 years has identified epigenetic mutations in men at specific sites within the DNA/mismatch repair genes (MMRs) accounting for 17% of men with dysfunctional sperm production (twice as frequent as Y chromosome microdeletions). Once commercially available and clinically validated in the Department of Urology at WCM, we believe this test will become one of the ASRM/AUA recommended genetic tests for all men with severe oligospermia or azoospermia. Phase 1 of the SBIR study will focus on 1) developing a highly accurate and cost-effective targeted sequencing assay for analysis of the novel epigenetic mutations identified by Dr. Lamb and 2) validating the assay in a CAP/CLIA laboratory using 200 samples from WCM. Phase 2 of this proposal will be dedicated to the development and commercialization of an LDT assay for use on all NOA patients treated at WCM.

摘要/摘要——固有生物科学 威尔康奈尔医学院 (WCM) 的多洛雷斯·兰姆 (Dolores Lamb) 博士发现了一种新的表观 男性不育症的遗传来源已被证明是最常见的遗传来源 患有非梗阻性无精子症 (NOA) 的男性精子受损。固有 Biosciences 与 WCM 合作提议开发一种具有成本效益的 用于对入院患者进行基因检测的商业诊断 WCM 泌尿科。 在此发现之前，克氏综合症和 Y 染色体微缺失被认为是 男性不育的两个最普遍的遗传原因。克氏综合征和 Y 无精子症男性中染色体微缺失分别占11%和8%。 根据现行的 AUA/ASRM 指南，对克兰费尔特综合征进行基因检测 建议所有患有严重少精子症或 无精症治疗前澄清男性不育症的病因（市场规模1220万） 全世界的男人）。 Lamb 实验室过去 20 年的工作已经发现了表观遗传突变 DNA/错配修复基因 (MMR) 内特定位点的男性占男性的 17% 精子生成功能障碍（是 Y 染色体微缺失的两倍）。一次 我们相信，该产品已在 WCM 泌尿外科上市并经过临床验证 该测试将成为 ASRM/AUA 推荐的针对所有患有严重疾病的男性的基因测试之一 少精症或无精症。 SBIR 研究的第一阶段将重点关注 1) 开发高度 准确且经济有效的靶向测序分析，用于分析新型表观遗传学 Lamb 博士发现的突变以及 2) 使用 CAP/CLIA 实验室验证检测结果 来自 WCM 的 200 个样本。该提案的第二阶段将致力于开发和 LDT 检测商业化，用于所有在 WCM 接受治疗的 NOA 患者。