Optimization of a Gene Therapy for Chronic Pain in Human DRGs

项目总结/摘要 该项目的目标是设计和优化一种基因治疗产品， 永久性，非成瘾性和持久的方式。有超过一亿的美国人 患有慢性疼痛，目前的治疗主要包括阿片类麻醉剂。然而，在这方面， 阿片类药物具有严重的副作用并且高度成瘾。电压门控钠通道 传递疼痛信号。遗传学研究发现一种罕见的遗传性 一个通道亚型（NaV1.7）的功能缺失突变，伴有一种罕见的遗传性疾病， 先天性疼痛不敏感症（CIP）因此，NaV1.7的选择性抑制可以重现 CIP的表型。然而，人类NaV蛋白的高度同源性， 努力开发选择性抑制剂。我们开发了一种创新的基因治疗方法 在体内靶向NaV1.7，并已在三种小鼠疼痛模型中证明其疗效。期间 在第一阶段SBIR中，我们将优化这种基因疗法，以靶向人类NaV1.7序列， 人类细胞系，然后我们将选择最佳设计在人类DRG神经元中进行测试 在离体化疗诱导的神经性疼痛模型中的效力、特异性和功效。 因此，Navega的最终目标是开发新的治疗方法，通过使用 特定的基因治疗方法，以提供阿片类药物的替代治疗慢性 痛苦

Project Summary/Abstract The goal of this project is design and optimize a gene therapy product that relieves pain in a non- permanent, non-addictive and long lasting manner. There are more than 100 million Americans suffering from chronic pain and current treatments consist mainly of opioid narcotics. However, opioids have severe side effects and are highly addictive. Voltage-gated sodium channels transmit pain signals in nociceptive neurons. Genetic studies have correlated a rare hereditary loss-of-function mutation in one channel isoform (NaV1.7) with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Thus, selective repression of NaV1.7 could recapitulate the phenotype of CIP. However, the high homology of human NaV proteins, have frustrated most efforts to develop selective inhibitors. We have developed an innovative gene therapy approach to target NaV1.7 in vivo, and have demonstrated its efficacy in three murine models of pain. During this Phase I SBIR, we will optimize this gene therapy to target the human NaV1.7 sequence in human cell lines, and then we will choose the best designs to test them in human DRG neurons for potency, specificity, and efficacy in an ex vivo chemotherapy-induced neuropathic pain model. Thus, Navega’s final goal is to develop novel therapeutics that can mitigate pain through the use of specific gene therapy approaches to provide an alternative treatment to opioids for chronic pain.