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: 8214640
• 负责人: ANDREAS S. BEUTLER
• 金额: $ 42.21万
• 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/8214640
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Afferent Neurons; American; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Breakthrough Pain; Canis familiaris; Catheters; Cervical; Clinical; Clinical Trials; Data; Development; Diffuse; Disease; Drug Delivery Systems; Endorphins; Evaluation; FDA approved; Femur; Fracture; Future; Gene Delivery; Gene Transfer; Genes; Home environment; Human; Human Development; IL10 gene; Immunity; Implant; Injection of therapeutic agent; Institution; Laboratories; Life; Malignant Neoplasms; Measures; Methods; Modeling; Morphine; Mutation; Nervous system structure; Neurons; Non-Rodent Model; Organ; Pain; Pain Research; Pain management; Pathology; Patients; Pharmaceutical Preparations; Population; Procedures; Rattus; Recombinant adeno-associated virus (rAAV); Research; Research Personnel; Rodent Model; Role; Route; Safety; Self Administration; Serological; Serotyping; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Ganglia; Spinal Puncture; Spinal Tap; Stable Disease; Symptoms; TNFR-Fc fusion protein; Testing; Time; Training; Translational Research; Translations; allodynia; cancer cell; cancer pain; chronic neuropathic pain; chronic pain; cisterna magna; cost; efficacy testing; functional outcomes; gene therapy; improved; meetings; mutant; novel; painful neuropathy; research study; therapeutic gene; therapeutic target; tibia; tool; vector

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 e3 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. PROJECT NARRATIVE 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.

腰椎穿刺（LP）是向神经系统提供新疗法的一种有吸引力的途径 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；并且有 未能瞄准神经元。我们已经开发出高效的基因转移到初级感官 背根神经节 (DRG) 的神经元通过 LP，即鞘内 (IT)，使用自我互补 重组腺相关病毒血清型 8 (sc-rAAV8)。 sc-rAAV8 的单次给药 表达镇痛基因前原-¿-内啡肽 (pp¿EP) 或大鼠抗-内啡肽的突变形式 炎症基因白细胞介素 10 (rIL10/F129S) 可显着 (p<0.0001) 缓解症状 在大鼠慢性神经病理性疼痛模型中持续三个月，这是一个重要的功能结果。这 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，用于治疗棘手的疾病 专业研究中心之外的临床医生可以使用慢性疼痛。为了 调查/确定临床转化的潜力，我们提出以下具体目标： 目标 1. 在封闭与开放 IT 空间中通过体视学量化 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，并确定是否存在 与传统疼痛治疗的药理学协同作用。目标 3. 测试镇痛作用 该方法在反映无法治愈的癌症患者疼痛的新大鼠模型中的功效 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 DRG 大型动物的神经元。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 亿美元的成本（如 PA-07-282 中所述）。这个应用程序 提出了一种基因治疗方法，如果研究计划成功，该方法将成为候选者 用于晚期恶性肿瘤严重疼痛患者的临床开发。 IT sc-rAAV8可能 作为机制验证试验的工具，例如验证小胶质细胞激活作为治疗靶点 在人类中，也可能成为治疗顽固性慢性疼痛的新药。项目叙述 慢性疼痛影响着 5000 万美国人，仅在美国每年就会造成超过 1000 亿美元的损失（如上所述） 在 PA-07-282 中）。脊髓穿刺是向神经系统提供新疗法的一种有吸引力的途径 多种疾病，尤其是疼痛。原因是脊髓具有疼痛门的功能，能够 打开以促进疼痛信号传递或关闭以控制疼痛。脊椎穿刺是 对患者安全；在床边进行；并获得 FDA 批准用于常规药物。我们开发了一个 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，我们发现在 大鼠模型显示，我们可以将严重类型的疼痛、慢性神经性疼痛控制超过 3 个月 方法。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 为了评估这是否是一种可行的治疗方法，可供未来开发用于人类 特别关注晚期癌症引起的剧烈疼痛。