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遗传性疾病，由一种名为SCN1A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，用基因治疗方法取代SCN1A一直受到与基因治疗活动相关的安全问题风险的阻碍，这些问题与大脑中特定组织之外的活动有关。该项目提出了一种独特的RNA编辑方法来替换SCN1A中的缺陷序列，仅在大脑内的特定组织和细胞类型中治疗Drave氏综合症。由此产生的方法可能形成第一个安全有效的基因疗法来治疗这种毁灭性的疾病。这种第一阶段的SBIR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。这个小型企业技术转让(STTR)第一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。我们将重点介绍Drave氏综合征，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靶向有缺陷的RNA，我们将设计一种方法，避免与异常离子通道表达相关的毒性风险。事实上，由于这种非靶标活动的风险，这种疾病已经抵制了基因替换方法。我们的系统还通过改变细胞结构的用途来避免使用免疫原性蛋白质和功能。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)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。

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.