Developing RNA therapeutics for rare neurodevelopmental disorders

项目摘要 开发RNA治疗罕见神经发育障碍 由单个基因突变引起的单基因疾病在个体上很罕见，但在集体上很常见， 占世界人口的10%。这些疾病中有许多是致残的，甚至是危及生命的， 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基因的获得 负面影响可导致病理学，基因表达的改变可改善疾病。大邑 Therapeutics，Inc是哥伦比亚大学医学中心的一个分支，其目标是精确地推进 用于治疗罕见单基因疾病特别是神经系统疾病的靶向RNA治疗剂 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，我们已经优先考虑了一系列导致严重神经发育障碍的靶基因， 巨大的未满足的医疗需求这些靶基因通常难以用当前方法靶向 但我们独特的技术可以鉴定出内源性的、天然存在的基因调控区域， 其可以通过不同的治疗方式（包括反义寡核苷酸（ASO））靶向。在这 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。 通过使用阿索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阿索药物筛选，以确定最 有效的ASO作为药物先导，然后进行一系列临床前研究，以验证其在纠正 使用患者来源的iPSC，脑 类器官和小鼠模型。ASO是一种成熟的治疗药物，具有高靶向性的优点， 特异性、明确的作用模式和从药物发现到临床部署的加速时间轴。如果 成功，这项研究将提供关键的第一步，开发一种新的阿索治疗，以满足未满足的医疗 需要，并且还可能作为治疗由以下原因引起的神经发育障碍的原理的证明： 各种基因的突变

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.