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

这项小型企业创新研究（SBIR）二期项目旨在开发一种安全有效的治疗小儿癫痫综合征的方法。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，在大多数患者中导致毁灭性的癫痫发作、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，但由于安全性问题，这些方法的广泛使用受到限制。该项目采用一种独特的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一种治疗方法，并将构成数十亿美元的市场。这个小企业创新研究（SBIR）二期项目的重点是开发一种RNA编辑方法，替代突变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，这是一种主要的遗传性疾病，可导致儿童复发性和破坏性癫痫发作。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有缺陷的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，由于这种脱靶活动的风险，这种疾病一直抵制基因替代方法。该公司的系统还避免使用免疫原性蛋白质和功能，通过重新利用细胞机制。结果是一个固有的非免疫原性系统，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（定期间隔聚集的短回文重复序列）。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.