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) 第二阶段项目旨在开发一种安全有效的治疗方法，用于治疗一种名为 Dravet 综合征的破坏性儿童癫痫症，这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。基因治疗是一种涉及替换突变 DNA 序列的方法，但由于安全问题，这些方法的广泛使用受到了限制。替换有缺陷的序列该项目将有助于为美国近 30,000 名患有这种疾病的患者开发治疗方法，并将构成一个价值数十亿美元的市场。 II 项目专注于开发一种 RNA 编辑方法，替换突变 RNA 中的缺陷序列，作为解决遗传性人类疾病的方法。该公司专注于 Dravet 综合征，这是一种显性遗传疾病，可导致复发性和毁灭性癫痫发作。 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来靶向有缺陷的 RNA，该公司将设计一种避免这种风险的方法。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来避免使用免疫原性蛋白质和功能。其结果是一个本质上非免疫原性的系统，它将避免与使用非人类转录因子或基因编辑系统（如 CRISPR）相关的各种安全风险。该奖项是 NSF 的法定使命，并具有通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。