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

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方法，用于治疗一种称为Dravet综合征的破坏性形式的儿科癫痫。德拉韦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，在大多数患者中会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，但这些方法的广泛使用受到安全问题的限制。该项目遵循一种独特的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发展。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，并将构成一个数十亿美元的市场。这个小型企业创新研究(SBIR)第二阶段项目的重点是开发一种RNA编辑方法，以取代突变RNA中的缺陷序列，作为解决遗传性人类疾病的一种手段。该公司专注于德拉韦综合征，这是一种主要遗传的疾病，会导致儿童反复发作和毁灭性的癫痫发作。Drave氏综合征是由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。通过用一个只在抑制性神经元中活跃的系统来定位有缺陷的RNA，该公司将设计出一种方法，避免与异常离子通道表达相关的毒性风险。事实上，由于这种非靶标活动的风险，这种疾病已经抵制了基因替换方法。该公司的系统还通过重新调整细胞机械的用途来避免使用免疫原蛋白和功能。其结果是一种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(成簇的规则间隔的短回文重复序列))相关的各种安全风险。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.