AAV-encoded analgesic peptide aptamers for chronic pain

AAV编码的镇痛肽适体治疗慢性疼痛

• 批准号: 9079673
• 负责人: Quinn H Hogan
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079673
• 关键词: Absence of pain sensation; Acquired Immunodeficiency Syndrome; Action Potentials; Address; Adult; Adverse effects; Affect; Afferent Neurons; Affinity; Age; Analgesics; Animal Experimentation; Animals; Arthritis; Behavioral; Binding; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Dose; Drug usage; Evaluation; Failure; Frequencies; Functional disorder; Generations; Genes; Health; Healthcare; Human; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Knee; Left; Malignant Neoplasms; Measures; Mediating; Mental Depression; Mental Health; Mission; Modeling; Molecular; Molecular Target; Nerve; Neurons; Nociception; Pain; Pain Measurement; Pain management; Pathway interactions; Peptide aptamers; Peptides; Performance; Peripheral; Peripheral nerve injury; Pharmaceutical Preparations; Physiological; Process; Proteins; Quality of life; RNA Interference; Rattus; Recombinant adeno-associated virus (rAAV); Recombinants; Recovery of Function; Rehabilitation therapy; Research; Role; Safety; Sensory; Signal Pathway; Signal Transduction; Signaling Protein; Site; Skin; Specificity; Spinal Ganglia; Staging; Stress; Synapses; System; Techniques; Testing; Therapeutic; Transgenes; Trauma; Vanilloid; Veterans; Viral; Viral Vector; Work; adeno-associated viral vector; animal pain; base; behavior test; chronic pain; cost; design; dorsal horn; efficacy testing; flexibility; gene therapy; in vivo; knock-down; neurotransmission; novel; novel strategies; novel therapeutics; pain behavior; protein protein interaction; public health relevance; receptor; research study; small molecule; success; synaptic function; targeted delivery; tool; trafficking; transgene expression; vector

 DESCRIPTION: Chronic pain is a critical limiting factor that delays rehabilitation after injury. Since currently available treatments are inadequate, the development of new therapeutics is a national healthcare priority. Years of animal experimentation have generated a multitude of mechanistic observations that explain the initiation and continuation of pain at a cellular and molecular level but new therapies have not emerged from this effort. Two key limitations are the nonspecific effects of typical small molecule drugs, and the inability to limit dangerous side effects caused by off-target actions when agents are delivered systemically. We have devised a solution that employs recombinant adeno-associated viral (AAV) vectors to express small analgesic peptides (called peptide aptamers) in sensory neurons following injection of the vector into the dorsal root ganglion (DRG). Substantial data show that injection at the level of the DRG is safe in animals and humans. This approach also employs only minute doses of agent, and restricts effects to the targeted peripheral sensory neurons of that segment. The peptide aptamers are designed to interfere with assembly, trafficking, or function of critical molecular targets that regulate peripheral sensory transduction and dorsal horn (DH) synaptic function, resulting in highly selective peripheral modulation of sensory neuron performance. This final feature is critical since genesis and perpetuation of chronic pain clearly involves plasticity in peripheral receptors and DH pain- transmitting synapses. The overall objective of this project is to define a novel strategy, AAV-delivered analgesic peptide aptamers, for modulating intracellular protein interactions of specific nociceptive pathways selectively in primary sensory neurons, and to test the efficacy of this approach as a molecular therapeutic tool for treating chronic pain. The proposed studies will test proof-of-concept on modulation of two critical pain signaling nodes, the N-type Ca2+ channel (CaV2.2) and the Transient Receptor Potential Vanilloid 1 (TRPV1) channel. Successful completion of the proposed research will set the stage for development of an entirely novel and functionally potent mode of segmental chronic pain therapy, and thereby convert the vast backlog of mechanistic discovery into practical treatments.

 产品说明： 慢性疼痛是延迟损伤后康复的关键限制因素。由于目前 由于现有的治疗方法不足，开发新的治疗方法是国家卫生保健的优先事项。多年的动物实验已经产生了大量的机制观察，解释了在细胞和分子水平上疼痛的开始和持续，但新的治疗方法还没有出现。两个关键的限制是典型的小分子药物的非特异性作用，以及当药剂被全身递送时，不能限制由脱靶作用引起的危险副作用。我们设计了一种解决方案，采用重组腺相关病毒（AAV）载体，将载体注射到背根后，在感觉神经元中表达小镇痛肽（称为肽适体 神经节（DRG）。大量数据表明，在DRG水平注射在动物和人类中是安全的。这种方法也只使用微量的药剂，并将作用限制在该段的靶向外周感觉神经元上。肽适体被设计为干扰调节外周感觉转导和背角（DH）突触功能的关键分子靶标的组装、运输或功能，从而导致感觉神经元性能的高度选择性外周调节。这最后一个特征是至关重要的，因为慢性疼痛的发生和持续明显涉及外周受体和DH疼痛传递突触的可塑性。该项目的总体目标是定义一种新的策略，AAV递送的镇痛肽适体，用于选择性地调节初级感觉神经元中特定伤害性通路的细胞内蛋白质相互作用，并测试这种方法作为治疗慢性疼痛的分子治疗工具的功效。拟议的研究将测试两个关键疼痛信号节点的调制概念验证，N型Ca2+通道（CaV2.2）和瞬时受体电位香草酸1（TRPV1）通道。拟议研究的成功完成将为开发一种全新的、功能强大的节段性慢性疼痛治疗模式奠定基础，从而将大量积压的机械发现转化为实际治疗。