Next Generation Gene Therapy for Refractory Pain

治疗难治性疼痛的下一代基因疗法

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要慢性疼痛影响美国超过2500万成年人，是残疾的主要原因。现在可用的疼痛治疗（例如阿片类药物）通常无效，并且与不可接受的副作用有关包括呼吸抑郁和成瘾。新疼痛治疗的主要目标是抑制感觉有选择地传递疼痛信号（伤害感受器）的神经元而不会影响其他涉及的神经元无害的感觉或中枢神经系统。但是，伤害感受器特定的治疗方法保持婴儿期。基于病毒的基因疗法在治疗难治性疼痛方面具有几种有吸引力的优势，由于可以设计病毒以输送各种分子，因此可以在本地或系统地进行管理并已获得食品药品监督管理局（Food and Drug Administration）的许多迹象。然而， Nocteptor特异性病毒工具目前不存在很大程度上是由于感觉的异质性使这些细胞独有的分子特征变得困难的神经元。最近的进步在单细胞基因组学中，使我们能够生成一个描述有选择性基因的细胞图集用小鼠和人伤害感受器表达。该建议旨在发现内源基因调节介导伤害感受器特异性基因表达模式的元素，并将这些元素设计为条形码腺相关病毒库。为此，我们提出以下特定目的：1）映射小鼠和人类中的伤害感受器特异性基因调节元件以及2）生成伤害感受器特异性的生成 AAV工具包。我们在该提案中开发的伤害感受器特异性病毒将立即对科学有用野生型小鼠和可能其他物种的伤害感受器的社区。此外，因为我们会优先考虑小鼠和人伤害感受器之间保守的基因调节元素，我们很乐观我们在小鼠中筛查的病毒还将驱动人类伤害性特异性基因表达。这些接下来一代伤害性特异性基因疗法将非常适合治疗某些难治性疼痛障碍因为它们可以通过标准门诊手术本地对神经性感觉神经节进行并且可以设计以驱动仅在存在下使伤害感受器活性沉默的离子通道的表达特定药物（化学遗传学）。这种无阿片类药物的方法可能具有重大的翻译应用对于难治性慢性疼痛的患者，他们通常没有其他缓解选择。