Developing RNA therapeutics for rare neurodevelopmental disorders

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.