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.

 描述： 慢性疼痛是延迟受伤后康复的关键限制因素。由于目前 可用的治疗不足，新治疗剂的发展是国家医疗保健的优先事项。多年的动物实验产生了大量的机械观察，这些观察力解释了细胞和分子水平上疼痛的主动性和延续，但是从这项工作中却没有出现新的疗法。两个关键的局限性是典型的小分子药物的非特异性效应，以及当代理系统地交付时，无法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，该解决方案采用重组腺相关的病毒（AAV）向量来表达小镇痛作用（称为肽适体）在将载体注射到背根后感觉神经元中 神经节（DRG）。大量数据表明，在动物和人类中，DRG水平的注射是安全的。这种方法还仅采用微量剂量的药物，并限制了该细分市场的靶向外围感觉神经元的影响。胡椒体的设计旨在干扰调节周围感觉转导和背角（DH）突触功能的临界分子靶标的组装，运输或功能，从而导致高度选择性的感官神经元性能的外围调制。这一最终特征至关重要，因为慢性疼痛的起源和永续化显然涉及外周受体和DH疼痛传播突触的可塑性。该项目的总体目的是定义一种新型策略，即降低了镇痛肽适体，以选择性地调节特定的伤害感受性途径的细胞内蛋白质相互作用，并在原发性感觉神经元中选择性地调节该方法作为一种分子治疗工具的有效性，用于治疗慢性疼痛。拟议的研究将测试两个关键疼痛信号节点的调节概念概念，即N型Ca2+通道（CAV2.2）和瞬态受体电位香草素1（TRPV1）通道。拟议研究的成功完成将为开发一种完全新颖且功能潜在的分段慢性疼痛疗法的模式奠定了基础，从而将机械发现的疫苗积压转换为实用治疗。