SBIR Phase II: Repurposing RNA processing factors to edit RNA for the treatment of Dravet syndrome

SBIR II 期：重新利用 RNA 加工因子编辑 RNA 以治疗 Dravet 综合征

• 批准号: 2334756
• 负责人: David Nelles
• 金额: $ 99.93万
• 依托单位: TACIT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2334756&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Repurposing; RNA

This Small Business Innovation Research (SBIR) Phase II project is the development of a safe and effective treatment for a devastating form of pediatric epilepsy called Dravet syndrome. Dravet syndrome is an inherited disease that is caused by mutations. This disease affects children and young adults and results in devastating seizures, developmental issues, and premature death in most patients. Gene therapy is an approach that involves replacement of mutated DNA sequences, but broad use of these approaches has been limited by safety issues. This project follows a unique RNA editing approach to replace defective sequences in the gene in order to halt or reverse the progression of this disease. This project will be instrumental in developing a treatment for nearly 30,000 patients in the U.S. with this condition and would constitute a multibillion-dollar market. This Small Business Innovation Research (SBIR) Phase II project focuses on the development of an RNA editing approach that replaces defective sequences within mutated RNAs as a means to address inherited human disease. The company focuses on Dravet syndrome, a dominantly inherited disease that causes recurrent and devastating seizures in children. Dravet syndrome is caused by mutations in SCN1A, which is an ion channel that is primarily expressed in inhibitory neurons. By targeting defective RNAs with a system that is active only in inhibitory neurons, the company will devise an approach that avoids the risk of toxicities associated with aberrant ion channel expression. Indeed, this disease has resisted gene replacement approaches due to this risk of off-target activities. The company’s system also avoids the use of immunogenic proteins and functions via repurposing of cellular machinery. The result is an inherently non-immunogenic systems which will avoid the varied safety risks associated with use of non-human transcription factor or gene editing systems such as CRISPR (clustered regularly interspaced short palindromic repeats).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个小企业创新研究（SBIR）第二阶段项目是开发一种安全有效的治疗小儿癫痫的破坏性形式称为Dravet综合征。Dravet综合征是一种由突变引起的遗传性疾病。这种疾病影响儿童和年轻人，并导致大多数患者的毁灭性癫痫发作，发育问题和过早死亡。基因治疗是一种涉及替换突变DNA序列的方法，但这些方法的广泛使用受到安全问题的限制。该项目采用独特的RNA编辑方法来替换基因中的缺陷序列，以阻止或逆转这种疾病的进展。该项目将有助于为美国近3万名患有这种疾病的患者开发治疗方法，并将构成一个数十亿美元的市场。这个小企业创新研究（SBIR）第二阶段项目的重点是开发一种RNA编辑方法，该方法取代突变RNA中的缺陷序列，作为解决遗传性人类疾病的一种手段。该公司专注于Dravet综合征，这是一种显性遗传疾病，可导致儿童反复发作和破坏性癫痫发作。Dravet综合征是由SCN1A突变引起的，SCN1A是一种主要在抑制性神经元中表达的离子通道。通过使用仅在抑制性神经元中活跃的系统靶向缺陷RNA，该公司将设计一种方法，避免与异常离子通道表达相关的毒性风险。事实上，由于这种脱靶活性的风险，这种疾病已经抵制了基因替代方法。该公司的系统还通过重新利用细胞机器来避免使用免疫原性蛋白质和功能。其结果是一个固有的非免疫原性系统，将避免与使用非人类转录因子或基因编辑系统，如CRISPR（成簇的定期间隔短回文重复序列）相关的各种安全风险。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。