STTR Phase I: Harnessing the power of introns for safe and effective therapeutics and genomic screening

这个小企业技术转让（STTR）第一阶段项目的更广泛的影响/商业潜力将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综合征是一种遗传性疾病，由称为SCN 1A的离子通道突变引起。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。事实上，用基因治疗方法替代SCN 1A已经被与脑中特定组织外的基因治疗活性相关的安全性问题的风险所阻碍。该项目提出了一种独特的RNA编辑方法来替换SCN 1A中的缺陷序列，仅在大脑内的特定组织和细胞类型中治疗Dravet综合征。由此产生的方法可能成为治疗这种毁灭性疾病的第一种安全有效的基因疗法。该I期SBIR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，并将构成数十亿美元的市场。 这个小企业技术转让（STTR）第一阶段项目的重点是开发一种RNA编辑方法，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。我们将重点介绍Dravet综合征，这是一种显性遗传性疾病，可导致儿童反复发作和破坏性癫痫发作。 Dravet综合征是由SCN 1A突变引起的，SCN 1A是一种主要在抑制性神经元中表达的离子通道。通过用仅在抑制性神经元中有活性的系统靶向缺陷RNA，我们将设计一种避免与异常离子通道表达相关的毒性风险的方法。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。我们的系统还避免了免疫原性蛋白质的使用和功能，通过细胞机器的再利用。该奖项反映了NSF的法定使命，并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，被认为值得支持。

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) Phase I project will be 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 in an ion channel called SCN1A. Gene therapy is an approach that involves replacement of mutated DNA sequences but broad use of these approaches have been limited by safety issues. Indeed, replacement of SCN1A with a gene therapy approach has been held back by the risk of safety issues associated with activity of the gene therapy outside of specific tissues in the brain. This project proposes a unique RNA editing approach to replace defective sequences in SCN1A, treating Dravet syndrome only in specific tissue and cell types within the brain. The resulting approach could form the first safe and effective gene therapy for this devastating disease. This Phase I SBIR will be instrumental towards developing a treatment for nearly 30,000 patients in the US with this condition and would constitute a multibillion-dollar market. This Small Business Technology Transfer (STTR) Phase I 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. We will focus 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, we 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. Our 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.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.