Next Generation Gene Therapy for Refractory Pain

治疗难治性疼痛的下一代基因疗法

• 批准号: 10553126
• 负责人: William Russell Renthal
• 金额: $ 71.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553126
• 关键词: Absence of pain sensation; Adult; Affect; Afferent Neurons; Animal Model; Atlases; Bar Codes; Bioinformatics; Biological Assay; Cell Nucleus; Cells; Central Nervous System; Characteristics; Chromatin; Chromatin Structure; Cognition; Communities; Dangerousness; Data; Distal; Elements; Engineering; Enhancers; Enterobacteria phage P1 Cre recombinase; Esthesia; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Transfer; Generations; Genes; Genetic; Genetic Transcription; Genomics; Goals; Heterogeneity; Histone Acetylation; Human; In Situ Hybridization; Intractable Pain; Ion Channel; Libraries; Maps; Mediating; Medicine; Molecular; Mus; Neurons; Neuropathy; Nociceptors; Opioid; Outpatients; Pain; Pain Disorder; Pain Research; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Procedures; Property; Refractory; Regulator Genes; Regulatory Element; Research; Resolution; Safety; Sensory Ganglia; Specificity; Spinal Ganglia; Therapeutic; Translating; Transposase; United States; United States Food and Drug Administration; Ventilatory Depression; Viral; Viral Vector; Virus; Wild Type Mouse; addiction; cell type; chronic pain; clinical pain; design; disability; epigenomics; experience; gene conservation; gene therapy; genome-wide; improved; in vivo; infancy; insight; next generation; optogenetics; pain model; pain signal; painful neuropathy; promoter; screening; selective expression; side effect; single nucleus RNA-sequencing; stem; tool; translational applications; transmission process

Project Summary Chronic pain affects over 25 million adults in the United States and is a major cause of disability. Currently available pain treatments such as opioids are often ineffective and associated with unacceptable side effects including respiratory depression and addiction. A major goal for new pain therapeutics is to inhibit the sensory neurons which transmit pain signals (nociceptors) selectively without affecting other neurons involved in innocuous sensation or the central nervous system. However, nociceptor-specific therapeutic approaches remain in their infancy. Viral-based gene therapy offers several attractive advantages in treating refractory pain, as viruses can be engineered to deliver a wide range of molecules, can be administered locally or systemically, and have been recently approved by the Food and Drug Administration for a number of indications. However, nociceptor-specific viral tools do not presently exist in large part due to the extraordinary heterogeneity of sensory neurons that has made it difficult to identify molecular features that are unique to these cells. Recent advances in single-cell genomics have enabled us to generate a cell atlas that describes the genes that are selectively expressed in mouse and human nociceptors. This proposal aims to uncover the endogenous gene regulatory elements that mediate nociceptor-specific gene expression patterns and engineer these elements into barcoded adeno-associated viral libraries. To accomplish this, we propose the following specific aims: 1) Mapping nociceptor-specific gene regulatory elements in mouse and human and 2) Generation of a nociceptor-specific AAV toolkit. The nociceptor-specific viruses we develop in this proposal will be immediately useful to the scientific community for accessing nociceptors in wild-type mice and likely other species. In addition, because we will prioritize gene regulatory elements that are conserved between mouse and human nociceptors, we are optimistic that the viruses we screen in mice will also drive nociceptor-specific gene expression in humans. These next generation nociceptor-specific gene therapies would be ideally suited for treating certain refractory pain disorders because they can be administered locally to neuropathic sensory ganglia through standard outpatient procedures and can be engineered to drive expression of ion channels that silence nociceptor activity only in the presence of a specific drug (chemogenetics). This opioid-free approach could have significant translational applications for patients with refractory chronic pain who often have no other options for relief.

项目概要 慢性疼痛影响美国超过 2500 万成年人，是导致残疾的主要原因。现在 现有的疼痛治疗方法（例如阿片类药物）通常无效，并且会产生不可接受的副作用 包括呼吸抑制和成瘾。新疼痛疗法的一个主要目标是抑制感觉 选择性地传递疼痛信号（伤害感受器）的神经元，而不影响参与疼痛的其他神经元 无害的感觉或中枢神经系统。然而，伤害感受器特异性治疗方法 仍处于婴儿期。基于病毒的基因疗法在治疗难治性疼痛方面具有几个有吸引力的优势， 因为病毒可以被设计来传递多种分子，可以局部或全身给药， 最近已获得美国食品和药物管理局的多项适应症批准。然而， 由于感觉的异常异质性，伤害感受器特异性病毒工具目前并不存在。 神经元使得识别这些细胞特有的分子特征变得困难。最新进展 单细胞基因组学中的研究使我们能够生成一个细胞图谱，该图谱描述了选择性地被识别的基因。 在小鼠和人类伤害感受器中表达。该提案旨在揭示内源基因调控 介导伤害感受器特异性基因表达模式的元件，并将这些元件设计成条形码 腺相关病毒文库。为了实现这一目标，我们提出以下具体目标：1）映射 小鼠和人类中伤害感受器特异性基因调控元件以及 2) 伤害感受器特异性的产生 AAV 工具包。我们在本提案中开发的伤害感受器特异性病毒将立即对科学有用。 用于访问野生型小鼠和可能的其他物种中的伤害感受器的群落。另外，因为我们将 优先考虑小鼠和人类伤害感受器之间保守的基因调控元件，我们很乐观 我们在小鼠体内筛选的病毒也将驱动人类伤害感受器特异性基因的表达。接下来这些 新一代伤害感受器特异性基因疗法将非常适合治疗某些难治性疼痛疾病 因为它们可以通过标准门诊程序局部给药于神经性感觉神经节 并且可以被设计为驱动离子通道的表达，从而仅在存在时沉默伤害感受器活动 特定药物（化学遗传学）。这种不含阿片类药物的方法可能具有重要的转化应用 适用于通常没有其他缓解方法的难治性慢性疼痛患者。