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

快速通道SBIR：确定和验证罕见疾病治疗干预的目标 中间代谢缺陷。 摘要 在实验室里研究和了解肝脏罕见疾病的生物学的可靠方法很少。 为了药物发现和开发的目的，这导致了开发的惨淡记录 新的治疗方法。首先，小鼠的遗传模型不能忠实地模仿人类罕见的疾病。第二，建模 体外肝脏疾病具有挑战性，因为原发性肝细胞癌的肝样表型迅速丧失。 肝细胞体外培养。由于这些原因，目标ID、验证和优先顺序可能具有误导性且代价高昂。在……里面 2014年，HemoSher、LLC和儿童国家健康系统结成战略合作伙伴关系，将 并加快罕见肝病的发现和治疗。HemoSear是一个早期阶段 拥有专利技术的生物技术公司，可在实验室中重现人类肝病生物学 使用人类原代细胞。儿童遗传和新陈代谢分部是一流的研究中心 拥有全国最大的研究和治疗肝脏罕见疾病患者的临床项目。在这下面 合作伙伴关系，我们已经表明，来自儿童医院治疗患者的生物材料可以用于验证 在HemoSher开发的用于确定治疗开发靶点的罕见疾病系统 作者声明：[Chapman et al，Mol.Gen.Metab.，2015年]。这项研究将重点放在一种名为 有机酸血症，特别是丙酸血症和甲基丙二酸血症。这些罕见的疾病 早期和晚期死亡率高，没有针对这些疾病的主要治疗方法，患者通常 接受肝脏移植以控制症状。此FastTrack SBIR的目的是识别、验证和 确定治疗中间代谢缺陷患者的治疗方法未来发展的优先目标 在肝脏里。

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.