Intrathecal Gene Transfer for Chronic Cancer Pain

鞘内基因转移治疗慢性癌痛

• 批准号: 7008903
• 负责人: ANDREAS S. BEUTLER
• 金额: $ 16.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008903
• 关键词: adeno associated virus group; analgesia; behavior test; biotechnology; cancer pain; chronic pain; densitometry; endorphins; fluorescence microscopy; gene delivery system; gene expression; gene therapy; genetic transcription; green fluorescent proteins; laboratory rat; nonhuman therapy evaluation; statistics /biometry; transfection /expression vector; western blottings

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.

描述（由申请人提供）：慢性疼痛是癌症的毁灭性后果，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疗法。然而，在相当多的患者中，由于药物的副作用，这些方法失败了。因此，开发不会引起全身阿片类药物常见副作用的癌症疼痛治疗方法仍然是一个重要目标。实现这一目标的一种已知策略是选择性地将具有阿片活性的药物递送至脊髓。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应用于人类。该候选者开发了一种人工治疗基因，前-β-内啡肽原（pp-β-EP），用于通过鞘内基因递送治疗疼痛，并在体外表征了其特性，并证明了其短期镇痛活性。急性疼痛的大鼠模型。该研究计划提出了一种策略，以实现适用于慢性癌痛的长期抗伤害作用。目的 1 是检验以下假设：鞘内注射的 rAAV 将在脊髓和/或脑膜内层细胞中建立长期转基因表达，并且血清型 1、2 和 5 在总体表达水平和/或转导的细胞范围。这些实验定义的最佳载体特征将应用于目标 2，以测试鞘内 pp-beta-EP 提供的假设：1) 在急性炎症疼痛模型中与全身吗啡产生镇痛协同作用，2) 在急性炎症疼痛模型中具有持久益处慢性癌症疼痛。目标 3 是评估鞘内 rAAV 和 pp-beta-EP 表达可能引起的免疫反应和其他毒性。该候选人拥有神经科学的研究背景，这是他在最近接受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，培训候选人负责任地进行研究，作为针对阿片类和非阿片类药物介导机制的慢性癌症疼痛的基因治疗和药物开发领域的调查员。