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）是一种有吸引力的途径，提供新的治疗神经系统 因为它对病人是安全的;在床边进行;和FDA批准的常规药物。 然而，迄今为止，其用于基因递送的使用一直无效;不符合安全原则;并且 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觉 通过LP，即鞘内（IT），使用自身互补的 重组腺相关病毒血清型8（sc-rAAV 8）。单次施用sc-rAAV 8 表达镇痛基因前内啡肽原（pp <$EP）或大鼠抗-内啡肽的突变形式， 炎性基因白细胞介素-10（rIL 10/F129 S）导致非常显著（p<0.0001）的症状缓解 在大鼠慢性神经性疼痛模型中持续E3个月，这是一个重要的功能结果。的 本申请假设是，通过LP的sc-rAAV 8是难治性肿瘤的可行基因递送产物， 慢性疼痛可由专业研究中心以外的临床医生使用。为了 为了调查/确定临床翻译的潜力，我们提出以下具体目标： 目标1.为了通过体视学定量DRG转导， 关闭 vs. 开放 IT空间，表征 对IT载体的血清免疫，并确定器官分布。目标2.识别 最强的候选治疗基因，并确定是否存在 与常规疼痛治疗的药理学协同作用。目标3.为了测试抗伤害性 这种方法在一种新的大鼠模型中的有效性反映了无法治愈的癌症患者的疼痛， 未来可能的临床试验方案。目标4。为了测试IT sc-rAAV 8是否有效地转导DRG 大型动物的神经元。意义和未来前景：慢性疼痛影响5000万美国人 并且仅在美国就产生> 1000亿美元/年的成本（如PA-07-282中所述）。本申请 提出了一种基因治疗方法，如果研究计划成功， 用于晚期恶性肿瘤重度疼痛患者的临床开发。IT sc-rAAV 8可以 作为机制验证试验的工具，例如，验证小胶质细胞活化作为治疗靶点 在人类中，也可能成为一种治疗顽固性慢性疼痛的新药。项目叙述 慢性疼痛影响5000万美国人，仅在美国每年就造成> 1000亿美元的费用（如前所述 在PA-07-282中）。脊椎穿刺是一种有吸引力的途径，可以为神经系统提供新的治疗方法， 各种疾病，尤其是疼痛。原因是脊髓的功能是 伤门 能够 大开，从而促进疼痛信号传递，或 密切 从而控制疼痛。脊椎穿刺是 对患者安全;在床边进行; FDA批准用于常规药物。我们已经开发出一种 通过脊椎穿刺给予新基因载体的基因治疗方法，其控制疼痛。具体来说，我们发现， 我们的大鼠模型可以将严重类型的疼痛、慢性神经性疼痛控制>3个月 approach.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， 为了评估，它是否是一个可行的治疗方法，为未来的发展，供人类使用， 特别关注晚期癌症的剧烈疼痛。