SBIR Phase I: Development of a genomic targeting drug delivery platform

这项小企业创新研究（SBIR）项目具有更广泛的影响/商业潜力，它是一项技术，能够开发出治疗一系列严重遗传神经退行性疾病的新疗法。提出的药物传递平台将有助于提高对某些遗传性神经退行性疾病的根本原因的理解。此外，治疗严重神经生成性疾病根本原因的新疗法将具有强大的商业潜力。目前，患者的治疗选择有限，需要大量且昂贵的支持性护理。新的治疗方法既可以改善患者的生活，又可以通过减少昂贵的医疗需求为保险公司创造价值。这个SBIR一期项目提出了一个基因组靶向给药平台的概念验证。基因组中不稳定的核苷酸重复序列已被确定为20多种神经退行性疾病的根本原因。这些是具有高疾病负担的衰弱性疾病，影响着数百万人的生命。大多数核苷酸重复扩增疾病是由单个等位基因的毒性功能获得突变引起的。这些疾病显示显性遗传，大多数患者有一个正常的，未受影响的拷贝。沉默疾病等位基因的表达将解决疾病的根本原因，完全阻止退行性症状的进展，并可能使患者恢复失去的功能。提出的努力旨在开发一种概念验证的等位基因特异性基因调节剂，使肌强直性营养不良1 （DMPK）中的突变等位基因沉默。利用这种药物传递平台，目标是合成针对患病DMPK等位基因的转录抑制因子的分子。利用患者细胞，该计划是测试在不影响健康拷贝的情况下抑制含有患病DMPK等位基因的重复表达的分子。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。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is a technology that enables the development of novel therapeutics to treat a range of serious genetic neurodegenerative diseases. The proposed drug delivery platform would help improve the understanding of the root cause of certain genetic neurodegenerative diseases. Further, new therapeutics to treat the root cause of severe neurogenerative disorders would have strong commercial potential. Currently, patients have limited treatment options and require significant and costly supportive care. New therapeutics would both improve the lives of patients and create value for insurance providers by reducing the need for costly care.This SBIR Phase I project proposes to demonstrate proof-of-concept for a genomic targeting drug-delivery platform. Unstable nucleotide repeats in the genome have been identified as the root cause of over 20 neurodegenerative conditions. These are debilitating disorders with high disease burden impacting millions of lives. Most nucleotide repeat expansion diseases are caused by a toxic gain-of-function mutation in a single allele. These diseases show dominant inheritance where most patients have a normal, unaffected copy. Silencing expression of the disease allele would address the root cause of the disease, completely halt progression of degenerative symptoms, and likely enable patients to regain lost function. The proposed effort seeks to develop a proof-of-concept allele-specific gene modulator that silences the mutant allele in myotonic dystrophy 1 (DMPK). Using this drug delivery platform, the objective is to synthesize molecules that would target transcriptional repressors specifically to the diseased DMPK allele. Using patient cells, the plan is to test for molecules that silence expression from the repeat containing diseased DMPK allele without impacting the healthy copy.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.