Intrathecal Gene Transfer for Chronic Cancer Pain

描述（由申请人提供）：慢性疼痛是癌症的破坏性后果，在疾病过程中影响大多数患者。常规治疗使用多种阿片类药物方案。然而，在相当数量的患者中，这些方法由于药物的不良反应而失败。因此，开发不引起全身阿片类药物常见副作用的癌症疼痛治疗仍然是一个重要目标。实现这一点的一种已知策略是将具有阿片样物质活性的药剂选择性递送至脊髓。基因转移技术，特别是腺相关病毒（AAV）的最新进展表明，基因治疗将在不久的将来安全地应用于人类。该候选人开发了一种人工治疗基因，前-β-内啡肽原（pp-beta-EP），用于通过鞘内基因递送治疗疼痛，在体外表征了其特性，并在大鼠急性疼痛模型中证明了其短期抗伤害活性。该研究计划提出了一种策略，以实现适用于慢性癌症疼痛的长期抗伤害效应。目的1是检验以下假设：鞘内注射的rAAV将在脊髓和/或脑膜衬里的细胞中建立长期转基因表达，并且血清型1、2和5将在总体表达水平和/或转导的细胞范围方面不同。这些实验定义的最佳载体特征将应用于目标2，以检验以下假设：鞘内注射pp-beta-EP提供1）在急性炎性疼痛模型中与全身吗啡的镇痛协同作用，以及2）在慢性癌症疼痛模型中的持久益处。目的3是评价鞘内rAAV和pp-β-EP表达可能引起的免疫应答和其他毒性。候选人具有神经科学的研究背景，这是他在最近的内科临床专业培训和肿瘤学亚专业培训之前获得的。拟议的研究将作为一个范例，以培养候选人在负责任的研究行为的职业生涯作为一个研究人员在基因治疗和药物开发领域的慢性癌症疼痛靶向阿片类药物和非阿片类药物介导的机制。

DESCRIPTION (provided by applicant): Chronic pain is a devastating consequence of cancer affecting the majority of patients during the course of the disease. Conventional treatments use a variety of opioid regimens. However, in a significant number of patients these approaches fail due to the adverse effects of the medication. Therefore, the development of cancer pain treatments that do not cause the common side effects of systemic opioids remains an important goal. One known strategy to achieve this is the selective delivery of agents with opioid activity to the spinal cord. Recent advances in gene transfer technology, in particular Adeno-Associated Virus (AAV), suggest that gene therapy will be available in the near future for safe application in humans. The candidate has developed an artificial therapeutic gene, pre-pro-beta-endorphin (pp-beta-EP) for the treatment of pain by intrathecal gene delivery, has characterized its properties in vitro, and has demonstrated its short-term antinociceptive activity in a rat model of acute pain. The research plan proposes a strategy to achieve a long-term antinociceptive effect applicable to chronic cancer pain. Aim 1 is to test the hypothesis that intrathecally-injected rAAV will establish long-term transgene expression in the cells of the spinal cord and/or meningeal linings and that the serotypes 1, 2 and 5 will differ in the overall expression level and/or the range of cells transduced. The optimal vector characteristics defined by these experiments will be applied in Aim 2 to test the hypotheses that intrathecal pp-beta-EP provides 1) analgesic synergy with systemic morphine in a model of acute inflammatory pain and 2) a durable benefit in a model of chronic cancer pain. Aim 3 is to evaluate the immune response and other toxicity that may be elicited by intrathecal rAAV and the expression of pp-beta-EP. The candidate has a research background in neuroscience that he acquired prior to his recent clinical specialty training in internal medicine and subspecialty training in oncology. The proposed research will serve as a paradigm to train the candidate in the responsible conduct of research for a career as an investigator in the areas of gene therapeutics and drug development for chronic cancer pain targeting opioid- and non-opioid mediated mechanisms.