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（由适用提供）：腰椎穿刺（LP）是为神经系统提供新疗法的有吸引力的途径，因为它在患者中是安全的；在床边表演；和FDA批准用于常规药物。但是，迄今为止，其用于基因输送的用途尚未有效。尚未符合安全原则；并且未能靶向神经元。我们使用LP（即使用自我弥补的重组腺相关病毒8（SC-RAAV8））开发了高效的基因转移到背根神经节（DRG）的主要感觉神经元（DRG）。表达镇痛基因prepro-endorphin（pp¿ep）的单一施用SC-RAAV8或大鼠抗炎基因介绍性基因介菌素100（RIL10/F129S）的突变形式导致了大比例慢性神经疗法疼痛模型，导致= 3个月的症状浮雕（p <0.0001）= 3个月。该应用的假设是，通过LP通过LP是一种可行的基因递送产品，可用于专业研究中心以外的临床医生可用的慢性疼痛。为了调查/确定临床翻译的潜力，我们提出以下特定目的：目标1。在“封闭”与“开放” IT空间中通过立体学量化DRG翻译，将血清学免疫学表征为IT载体，并确定器官分布。目的2。在神经性疼痛模型中确定强大的候选治疗基因，并定义是否存在与常规疼痛治疗的药物协同作用。目的3。在新的大鼠模型中测试该方法的抗吸毒性有效性，反映了无法治愈的癌症患者的疼痛，这可能是未来的临床试验筛查。目标4。测试它是否有效地翻译了大动物中的DRG神经元。意义与未来的观点：仅在美国，慢性疼痛就会影响5000万美国人，而慢性疼痛的成本高于1000亿美元（如PA-07-282所述）。该应用提出一种基因疗法方法，如果研究计划成功，该方法将成为高级恶性肿瘤严重疼痛患者的临床发育的候选人。 IT SC-RAAV8可以用作机械验证试验的工具，例如验证小胶质细胞激活是人类的治疗靶标，并且也可能成为其他棘手的慢性疼痛的新药。 公共卫生相关性：慢性疼痛会影响5000万美国人，仅在美国，就会造成> 1000亿美元的成本（如PA-07-282所述）。脊柱水龙头是为神经系统提供各种疾病但尤其是疼痛的一种有吸引力的途径。原因是脊髓作为“疼痛门”的作用，可以打开，从而促进疼痛信号转移或“关闭”，从而控制疼痛。患者的脊柱水龙头是安全的。在床边表演；和FDA批准用于常规药物。我们已经开发了一种基因治疗方法，该方法通过控制疼痛的脊髓水龙头来管理新的基因载体。具体而言，我们在大鼠模型中发现，通过我们的方法可以控制慢性神经性疼痛的严重类型，可以控制3个月。在本申请中提出的研究中，我们希望进一步研究和改进我们的方法以评估，这是否是一种可行的治疗方法，用于未来开发人类使用，特别关注晚期癌症的严重疼痛。