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

项目摘要：这个R21/R33转化衰老研究鉴定奖的主要目标 正在开发、优化和验证一种新基于基因治疗的治疗方法，用于治疗 老年人。疼痛是一个主要的社会经济问题，影响超过25%的美国成年人。 缺乏有效的疼痛治疗方法助长了阿片类药物的流行。对于老年患者，治疗 由于医疗条件也阻止了特定药物的使用， 由于多种药物的副作用的风险增加。来自人类遗传学和小鼠的证据 模型表明，减少初级痛觉神经元（伤害感受器）的放电足以 消除痛苦我们首先设计了新的机制，用于将AAV特异性地递送到伤害感受器。我们 然后开发新的方法来减少伤害性感受器放电，我们使用 小鼠原代伤害感受器和衍生的伤害感受器的全细胞膜片钳电生理学 从人类诱导多能干细胞。我们在老年动物中验证疼痛模型，并获得证据- 在老年动物中使用疼痛模型的基于AAV的治疗策略的概念有效性。的 该项目的成功完成为基于AAV的持续临床前开发奠定了基础。 治疗老年人的顽固性疼痛。

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.