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

致力于治疗老年人剧烈疼痛的精准基因疗法

基本信息

批准号：
10354349
负责人：
Brian Jason Wainger
金额：
$ 24.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354349
关键词：
Adult Adverse effects Affect Aging Animal Model Animals Award Behavioral Bioinformatics Biology Candidate Disease Gene Cell model Cells Clinical Congenital Pain Insensitivity Contralateral Data Development Dose Drug usage Elderly Electrophysiology (science)Gene Transduction Agent Genes Genetic Models Genetic Transcription Goals Human Human Genetics Impairment Individual Inflammatory Arthritis Inherited Injections Intra-Articular Injections Intractable Pain Intramuscular Injections Ipsilateral Knock-out Label Measures Medical Molecular Motor Neurons Mus Neuropathy Nociceptors Pain Pain management Pathologic Phase Phenotype Physiological Polypharmacy Postoperative Pain Potassium Channel Prevalence Promoter Regions Research Reverse Transcriptase Polymerase Chain Reaction Risk Route Safety Serotyping Signal Transduction Sodium Channel Specificity Spinal Cord Spinal Ganglia Testing Toxic effect Transcript Translations Validation Voltage-Gated Potassium Channel aged base cell type chronic pain comorbidity cost dermatome design effective therapy experience gain of function mutation gene therapy in vivo induced pluripotent stem cell knock-down mouse model nerve stem cell novel novel strategies older patient opioid epidemic overexpression pain model pain signal patch clamp preclinical development prevent promoter side effect socioeconomics stem cell model targeted treatment treatment optimization treatment strategy voltage

项目摘要

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.

项目摘要：R21/R33 转化衰老研究鉴定奖的主要目标正在开发、优化和验证一种基于基因治疗的新型治疗方法，用于治疗难治性疼痛年长的个体。疼痛是一个主要的社会经济问题，影响着超过 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碍了特定药物的使用，选择更加有限由于多重用药导致副作用的风险增加。来自人类遗传学和小鼠的证据模型表明，减少初级痛感神经元（伤害感受器）的放电就足以消除疼痛。我们首先设计新的机制，专门向 AAV 传递伤害感受器。我们然后开发新的方法来减少伤害感受器的放电，并且我们使用以下方法验证了这种减少原代小鼠伤害感受器和衍生伤害感受器的全细胞膜片钳电生理学来自人类诱导多能干细胞。我们验证老年动物的疼痛模型，并获得证据- 使用老年动物疼痛模型进行基于 AAV 的治疗策略的概念疗效。这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难治性疼痛。