Clinical epigenetic diagnostic for spermatogenic failure and future health risks

总结/摘要-固有生物科学 来自威尔康奈尔医学中心（WCM）的多洛雷斯·兰姆博士发现了一种新的肾上腺素， 男性不育的遗传来源，已被证明是最常见的遗传来源， 患有非阻塞性无精子症（NOA）的男性的精子损伤。固有 Biosciences与WCM合作，建议开发一种具有成本效益的 商业诊断，用于在疾病管理局对入院患者进行基因检测。 WCM的泌尿科。 在这一发现之前，Klinefelter综合征和Y染色体微缺失是 男性不育的两个最普遍的遗传原因。Klinefelter综合征和Y 染色体微缺失在无精子症男性中分别占11%和8%。 根据目前的AUA/ ASRM指南，Klinefelter综合征的基因检测 Y染色体微缺失被推荐用于所有严重少精子症的男性， 无精子症，在治疗前明确男性不育症的病因（市场规模为1220万 全世界的男人）。 Lamb实验室在过去20年的工作中发现了表观遗传突变， 男性在DNA/错配修复基因（MMR）内的特定位点占男性的17% 精子产生功能障碍（Y染色体微缺失的两倍）。一旦 我们认为， 这项测试将成为ASRM/AUA推荐的所有严重男性的基因测试之一。 少精子症或无精子症。SBIR研究的第一阶段将侧重于1）开发一个高度 用于分析新的表观遗传学的准确且具有成本效益的靶向测序测定 Lamb博士鉴定的突变和2）在CAP/CLIA实验室中使用 来自WCM的200个样本。本提案的第二阶段将致力于开发和 LDT测定商业化，用于在WCM治疗的所有NOA患者。

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.