Toward Precision Gene Therapy for Treatment of Severe Pain in Older Individuals

项目摘要：R21/R33翻译衰老研究鉴定奖的主要目标 正在开发、优化和验证一种新的基于基因治疗的顽固性疼痛治疗方法 年纪较大的个体。疼痛是一个主要的社会经济问题，影响着美国超过25%的成年人。 缺乏有效的疼痛治疗助长了阿片类药物的流行。在老年患者中，治疗 选择甚至更有限，因为医疗条件也阻止了特定药物的使用 因为多药联用会增加副作用的风险。来自人类遗传学和老鼠的证据 模型表明，减少初级痛觉神经元(伤害性感受器)的放电足以 消除痛苦。我们首先设计了新的机制来传递给AAVs，特别是伤害性感受器。我们 然后开发新的方法来减少伤害性感受器的放电，我们使用 小鼠初级伤害性感受器和衍生伤害性感受器的全细胞膜片钳电生理学 来自人类诱导的多能干细胞。我们验证了老年动物的疼痛模型，并获得了证据- 使用老年动物疼痛模型的基于AAV的治疗策略的概念外疗效。这个 该项目的成功完成为以AAV为基础的继续临床前开发奠定了基础 治疗老年人顽固性疼痛。

Project Summary: The primary goal of this R21/R33 Translational Aging Research Identification award is develop, optimize, and validate a novel gene therapy-based treatment approach for refractory pain in older individuals. Pain is a major socioeconomic problem, affecting more than 25% of adults in the US. The lack of effective treatments for pain has fueled the opioid epidemic. In elderly patients, treatment options are even more limited, on account of medical conditions that prevent specific drug use as well as increased risks of side effects due to polypharmacy. Evidence from human genetics and mouse models suggests that reducing firing in primary pain-sensing neurons, nociceptors, is sufficient to abrogate pain. We first design new mechanisms for delivering to AAVs specifically to nociceptors. We then develop novel approaches to decrease nociceptor firing, and we validate this reduction using whole cell patch clamp electrophysiology in both primary mouse nociceptors and nociceptors derived from human induced pluripotent stem cells. We validate pain models in aged animals, and obtain proof- of-concept efficacy for the AAV-based treatment strategy using the pain models in aged animals. The successful completion of the project sets the stage for continued preclinical development of AAV-based therapy for refractory pain in older individuals.