Optimization of a Gene Therapy for Chronic Pain in Human DRGs

项目摘要/摘要 该项目的目标是设计和优化一种基因治疗产品，可以缓解非癌症患者的疼痛 永久的，不上瘾的，持久的方式。有超过1亿的美国人 患有慢性疼痛，目前的治疗主要是阿片类麻醉剂。然而， 阿片类药物有严重的副作用，并极易上瘾。电压门控钠通道 在伤害性神经元中传递疼痛信号。遗传学研究发现了一种罕见的遗传病 一种罕见的遗传性疾病的单通道亚型(Nav1.7)功能丧失突变 先天性疼痛不敏感(CIP)。因此，对Nav1.7的选择性抑制可以概括为 CIP的表型。然而，人类NAV蛋白的高度同源性，最令人沮丧的是 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，并已在三种疼痛小鼠模型中证明了其有效性。在.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，然后我们将选择最好的设计在人类背根神经节神经元中测试它们 用于体外化疗诱导的神经病理性疼痛模型的效力、特异性和有效性。 因此，Navega的最终目标是开发新的疗法，通过使用 为慢性阿片类药物提供替代治疗的特定基因治疗方法 疼痛。

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.