Identification and validation of targets for therapeutic intervention in rare diseases of intermediary metabolism

快速SBIR：识别和验证罕见疾病治疗干预的靶点， 中间代谢缺陷。 摘要 在实验室研究和了解肝脏罕见病生物学的可靠方法很少 为了药物发现和开发的目的，这导致了药物开发的惨淡记录。 新疗法首先，遗传小鼠模型不能忠实地模仿人类罕见疾病。第二，建模 体外肝病是具有挑战性的，因为原发性肝癌的肝样表型的快速丧失， 体外肝细胞。由于这些原因，目标ID、验证和优先级排序可能会产生误导，而且成本很高。在 2014年，HemoShear，LLC和儿童国家卫生系统建立了战略合作伙伴关系， 并加速罕见肝脏疾病的发现和治疗。HemoShear是早期阶段 生物技术公司拥有在实验室中重现人类肝病生物学的专利技术 使用人类原代细胞。儿童遗传学和代谢部是一个重要的研究中心， 拥有全国最大的临床项目，研究和治疗肝脏罕见疾病患者。根据本 合作伙伴关系，我们已经表明，在儿童医院接受治疗的患者的生物材料可以用于验证 HemoShear开发的罕见病系统，用于识别治疗开发的靶点 [Chapman等人，Mol. Metab将军，2015年]。这项研究将集中在生物化学组的疾病， 有机酸血症，特别是丙酸血症和甲基丙二酸血症。这些罕见疾病 早期和晚期死亡率高，这些疾病没有主要治疗方法，患者通常 进行肝脏移植以控制症状本FastTrack SBIR的目的是识别、验证和 优先考虑未来治疗中间代谢缺陷患者的治疗方法的目标 在肝脏中。

Fast-Track SBIR: Identification and validation of targets for therapeutic intervention in rare diseases of intermediary metabolism defects. ABSTRACT There are very few reliable methods to study and understand the biology of liver rare diseases in the laboratory for the purpose of drug discovery and development, which contributes to a dismal record for development of new treatments. First, genetic mouse models do not faithfully mimic human rare diseases. Second, modeling liver diseases in vitro is challenging on account of the rapid loss of the liver-like phenotype of primary hepatocytes in vitro. For these reasons, target ID, validation and prioritization can be misleading and costly. In 2014, HemoShear, LLC and Children's National Health System formed a strategic partnership to systematize and accelerate discovery and treatments for rare diseases of the liver. HemoShear is an early stage biotechnology company with a patented technology for recreating human liver disease biology in the laboratory using human primary cells. The Division of Genetics and Metabolism at Children's is a premier research center with the nation's largest clinical program that studies and treats patients with liver rare diseases. Under this partnership, we have already shown that biomaterial from patients treated at Children's can be used to validate the rare disease system developed at HemoShear for the identification of targets for therapeutic development [Chapman et al, Mol. Gen. Metab., 2015]. This study will focus on the biochemical group of diseases called organic acidemias, specifically propionic acidemia and methylmalonic acidemia. These rare diseases have high early and late mortality rates, there are no primary therapies for these conditions and patients often undergo liver transplant to control symptoms. The purpose of this FastTrack SBIR is to identify, validate and prioritize targets for the future development of therapies to treat patients with intermediary metabolism defects in the liver.