sc-rAAV8 via Lumbar Puncture as Spinal Analgesic Drug Delivery Systems

sc-rAAV8 通过腰椎穿刺作为脊髓镇痛药物输送系统

• 批准号: 7869140
• 负责人: ANDREAS S. BEUTLER
• 金额: $ 34.13万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-16 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869140
• 关键词: Analgesics; Drug Delivery Systems; Spinal; Spinal Puncture

DESCRIPTION (provided by applicant): Lumbar puncture (LP) is an attractive route for delivering novel therapies to the nervous system because it is safe in patients; performed at the bedside; and FDA-approved for conventional drugs. However, its use for gene delivery has to date been ineffective; has not met safety principles; and has failed to target neurons. We have developed highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) via LP, i.e. intrathecally (IT), using self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8). A single administration of sc-rAAV8 expressing the analgesic gene prepro-¿-endorphin (pp¿EP) or a mutant form of the rat anti- inflammatory gene interleukin-10 (rIL10/F129S) led to highly significant (p<0.0001) relief of symptoms for =3 months in a rat chronic neuropathic pain model, an important functional outcome. The hypothesis of this application is that sc-rAAV8 via LP is a viable gene delivery product for intractable chronic pain usable by clinicians outside of specialized research centers. In order to investigate/establish the potential for clinical translation, we propose the following Specific Aims: Aim 1. To quantify DRG transduction by stereology in the "closed" vs. "open" IT space, characterize serological immunity to the IT vector, and determine organ distribution. Aim 2. To identify the strongest candidate therapeutic gene in the neuropathic pain model and to define if there is pharmacological synergy with conventional pain treatments. Aim 3. To test the antinociceptive efficacy of the approach in a new rat model reflecting pain in patients with incurable cancer, a possible future clinical trial-scenario. Aim 4. To test if IT sc-rAAV8 effectively transduces DRG neurons in large animals. Significance & future perspective: Chronic pain affects 50 million Americans and incurs costs of >$100 billion/year in the US alone (as stated in PA-07-282). This application proposes a gene therapy approach, which, if the Research Plan succeeds, will become a candidate for clinical development in patients with severe pain from advanced malignancies. IT sc-rAAV8 may serve as a tool for proof-of-mechanism trials, e.g. to validate microglial activation as therapeutic target in humans, and may also become a new drug for otherwise intractable chronic pain. Public Health Relevance: Chronic pain affects 50 million Americans and incurs costs of >$100 billion/year in the US alone (as stated in PA-07-282). Spinal tap is an attractive route for delivering novel therapies to the nervous system for a variety of diseases but particularly for pain. The reason is that the spinal cord functions as a "pain gate" able to open wide and thereby to facilitate pain signal transfer or to "close" and thereby control pain. A spinal tap is is safe in patients; performed at the bedside; and FDA-approved for conventional drugs. We have developed a gene therapy method administering new gene vectors by spinal tap, which control pain. Specifically, we find in a rat model that a severe type of pain, chronic neuropathic pain can be controlled for >3 months by our approach. In the research proposed in this application, we wish to study and improve our approach further in order to evaluate, whether it is a viable treatment approach for future development for human use with a special focus on severe pain from advanced cancer.

描述（由申请人提供）：腰椎穿刺（LP）是一种向神经系统提供新疗法的有吸引力的途径，因为它对患者是安全的；在床边进行；并获得 FDA 批准用于常规药物。然而，迄今为止，其用于基因传递的效果还不够。不符合安全原则；并且未能针对神经元。我们使用自我互补重组腺相关病毒血清型 8 (sc-rAAV8)，通过 LP（即鞘内 (IT)）将基因高效转移至背根神经节 (DRG) 的初级感觉神经元。在大鼠慢性神经病理性疼痛模型中，单次施用表达镇痛基因前原-内啡肽（pp-EP）或突变形式的大鼠抗炎基因白细胞介素-10（rIL10/F129S）的sc-rAAV8可导致症状高度显着（p<0.0001）缓解3个月，这是一个重要的功能结果。该应用的假设是，通过 LP 的 sc-rAAV8 是一种可行的基因递送产品，可用于专业研究中心之外的临床医生用于治疗顽固性慢性疼痛。为了研究/确定临床转化的潜力，我们提出以下具体目标： 目标 1. 通过体视学在“封闭”与“开放”IT 空间中量化 DRG 转导，表征对 IT 载体的血清学免疫，并确定器官分布。目标 2. 确定神经性疼痛模型中最强的候选治疗基因，并确定与传统疼痛治疗是否存在药理学协同作用。目标 3. 在反映无法治愈的癌症患者疼痛的新大鼠模型中测试该方法的镇痛功效，这是未来可能的临床试验场景。目标 4. 测试 IT sc-rAAV8 是否有效转导大型动物的 DRG 神经元。意义和未来展望：慢性疼痛影响着 5000 万美国人，仅在美国每年就会产生超过 1000 亿美元的费用（如 PA-07-282 中所述）。该申请提出了一种基因治疗方法，如果研究计划成功，该方法将成为晚期恶性肿瘤严重疼痛患者临床开发的候选方法。 IT sc-rAAV8 可以作为机制验证试验的工具，例如验证小胶质细胞激活作为人类的治疗靶点，并且也可能成为治疗其他棘手的慢性疼痛的新药。 公共健康相关性：慢性疼痛影响着 5000 万美国人，仅在美国每年就会产生超过 1000 亿美元的费用（如 PA-07-282 中所述）。脊髓穿刺是一种向神经系统提供新疗法的有吸引力的途径，可治疗多种疾病，尤其是疼痛。原因是脊髓起着“疼痛之门”的作用，能够张开从而促进疼痛信号传递，或者“关闭”从而控制疼痛。脊椎穿刺对患者来说是安全的；在床边进行；并获得 FDA 批准用于常规药物。我们开发了一种基因治疗方法，通过脊髓穿刺施用新的基因载体来控制疼痛。具体来说，我们在大鼠模型中发现，通过我们的方法可以将严重类型的慢性神经性疼痛控制超过 3 个月。在本申请提出的研究中，我们希望进一步研究和改进我们的方法，以评估它是否是未来人类使用的可行治疗方法，特别关注晚期癌症引起的严重疼痛。