Developing RNA therapeutics for rare neurodevelopmental disorders

项目总结 开发治疗罕见神经发育障碍的RNA疗法 由单基因突变引起的单基因疾病个别罕见，但共同影响。 占世界人口的10%。这些疾病中有许多是致残的，甚至危及生命，没有可用的 治疗。潜在的分子机制各不相同。基因功能的丧失和毒性或显性的获得 负效应可能导致病理，而基因表达的改变可能是疾病的修饰。大邑 Treateutics，Inc.是从哥伦比亚大学医学中心剥离出来的，其目标是精确地推进 靶向RNA疗法用于治疗罕见的单基因疾病，特别是神经疾病 影响大脑和行为。使用我们的学术合作开发的专有目标发现平台- 创始人们，我们已经优先列出了导致严重神经发育障碍的目标基因清单 巨大的未得到满足的医疗需求。这些靶基因通常很难用目前的方法进行靶向。 而是可以用我们独特的技术来识别内源性的、自然发生的基因调节区 这可以被不同的治疗方式所靶向，包括反义寡核苷酸(ASO)。在这 建议，我们的目标是开发第一种治疗严重发育和智力残疾综合征的药物 通过使用ASO恢复基因表达和蛋白质功能。我们的方法的可行性得到了支持 通过令人信服的初步数据。我们建议进行系统的ASO药物筛查，以确定大多数 有效的ASO作为药物先导，然后进行一系列临床前研究，以验证其纠正 使用患者来源的IPSCs脑突变导致的分子、细胞和行为缺陷 有机化合物和老鼠模型。ASO是一种公认的治疗药物，具有靶向性高的优点。 特异性，明确的行动模式，以及加快从药物发现到临床部署的时间表。如果 这项研究的成功将为开发一种新的ASO疗法提供关键的第一步，以实现未获满足的医学 需要，并可能作为治疗由以下原因引起的神经发育障碍的原则证据 一系列基因的突变。

PROJECT SUMMARY Developing RNA therapeutics for rare neurodevelopmental disorders Monogenic diseases caused by mutations in single genes are individually rare, but collectively common affecting 10% of the world population. Many of these diseases are disabling or even life threatening with no available treatment. The underlying molecular mechanisms vary. Both loss of gene function and gain of toxic or dominant negative effects can lead to pathology, and modification of gene expression could be disease modifying. DAYI Therapeutics, Inc is a spin-out of Columbia University Medical Center that has the goal of advancing precisely targeted RNA therapeutics for the treatment of rare monogenic diseases, especially neurological disorders affecting the brain and behavior. Using a proprietary target discovery platform developed by our academic co- founders, we have prioritized a list of target genes causing severe neurodevelopmental disorders with tremendous unmet medical needs. These target genes are in general difficult to target with current approaches but are druggable with our unique technology to identify endogenous, naturally occurring gene regulatory regions that can be targeted by different therapeutic modalities including antisense oligonucleotides (ASOs). In this proposal, we aim to develop the first therapeutic for a severe developmental and intellectual disability syndrome by restoring gene expression and protein function using an ASO. The feasibility of our approach is supported by compelling preliminary data. We propose to perform a systematic ASO drug screen to identify the most effective ASOs as drug lead and then conduct a series of pre-clinical studies to validate their efficacy in correcting the molecular, cellular and behavioral deficits caused by the mutation using patient-derived iPSCs, brain organoids and mouse models. ASOs are an established therapeutic agent with the advantage of high target specificity, clear mode of action, and accelerated timeline from drug discovery to clinical deployment. If successful, this study will provide the critical first step to develop a novel ASO therapeutic to fulfill unmet medical needs and potentially also serve as proof of principle for treatment of neurodevelopmental disorders caused by mutations in a wide range of genes.