Developing RNA therapeutics for rare neurodevelopmental disorders

开发罕见神经发育障碍的 RNA 疗法

基本信息

批准号：
10697291
负责人：
Francesco Lotti
金额：
$ 29.95万
依托单位：
DAYI THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697291
关键词：
Academic Medical Centers Acceleration Affect Alleles Antisense Oligonucleotides Behavior Behavioral Biological Models Brain Cell Proliferation Chemistry Clinical Clinical Drug Development Clinical Trials Code DNA Methylation Data Developmental Delay Disorders Developmental Disabilities Disease Dominant-Negative Mutation Dose Drug Delivery Systems Drug Screening Drug Targeting Exons Gene Expression Gene Modified Gene Proteins Genes Genomic Segment Goals Growth Heterozygote Human Human Cell Line In Vitro Incidence Individual Injections Intellectual functioning disability Knowledge Lead Life Live Birth Loss of Heterozygosity Medical Mendelian disorder Messenger RNA Mission Modality Modeling Molecular Mus Mutation Neurodevelopmental Disorder Nonsense-Mediated Decay Nuclear Receptors Nucleic Acid Regulatory Sequences Open Reading Frames Organoids Pathology Patients Pharmaceutical Preparations Phase Poison Population Privatization Production Protein Isoforms Protein Structure Initiative Proteins RNA Splicing RNA-targeting therapy Regulator Genes Resolution Resources Risk SET Domain Seizures Series Site Small Business Technology Transfer Research Sotos syndrome Specificity Spinal Muscular Atrophy Supportive care Syndrome Technology Terminator Codon Tertiary Protein Structure Therapeutic Therapeutic Agents Therapeutic Effect Transcript Up-Regulation Validation Walking autism spectrum disorder clinical development de novo mutation developmental disease disabling disease disease-causing mutation dravet syndrome drug discovery effective therapy efficacy evaluation efficacy validation experimental study gene function gene therapy histone methyltransferase in vivo induced pluripotent stem cell innovation lead candidate loss of function mutation meetings microdeletion mind control mouse model nervous system disorder novel pre-Investigational New Drug meeting pre-clinical preclinical study programs protein function receptor binding success therapeutic RNA timeline uptake

项目摘要

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.

项目摘要为罕见神经发育疾病开发RNA疗法由单个基因突变引起的单基因疾病是个别罕见的，但统一影响占世界人口的10％。这些疾病中的许多疾病正在致残甚至威胁生命，没有可用治疗。潜在的分子机制各不相同。基因功能的丧失和有毒或显性的增益负面影响可能导致病理学，基因表达的改变可能是疾病的改变。 Dayi Therapeutics，Inc是哥伦比亚大学医学中心的衍生产品，其目的是精确前进靶向RNA疗法用于治疗罕见单基因疾病，尤其是神经系统疾病影响大脑和行为。使用我们的学术共同开发的专有目标发现平台创始人，我们优先考虑靶基因列表，导致严重的神经发育障碍巨大的未满足医疗需求。这些靶基因通常很难用当前方法靶向但是，我们的独特技术可以识别内源性，自然存在的基因调节区域这可以由不同的治疗方式来靶向，包括反义寡核苷酸（ASO）。在这个提案，我们旨在为严重的发育和智力疾病综合征开发第一种治疗方法通过使用ASO恢复基因表达和蛋白质功能。支持我们方法的可行性通过引人注目的初步数据。我们建议执行系统的ASO药物屏幕以识别最多有效的ASO作为药物铅，然后进行一系列临床前研究，以验证其校正功效使用患者衍生的IPSC突变引起的分子，细胞和行为缺陷，大脑器官和小鼠模型。 ASO是一种已建立的治疗剂，具有高目标的优势特异性，清晰的作用方式以及从药物发现到临床部署的加速时间表。如果成功，这项研究将为开发新颖的ASO治疗性提供未满足医学的关键第一步需求并有可能作为治疗神经发育障碍的原理证明广泛基因的突变。