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

基本信息

批准号：
8049101
负责人：
ANDREAS S. BEUTLER
金额：
$ 44.2万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/8049101
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 public health relevance research study therapeutic gene therapeutic target tibia tool vector

项目摘要

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，因为它在床边进行；并且 FDA 批准了其用于基因治疗。迄今为止，递送无效；尚未高度满足安全原则；并且未能通过 LP（即鞘内注射）靶向神经元。 (IT)，使用自我互补重组腺相关病毒血清型 8 (sc-rAAV8) 表达镇痛基因 prepro-¿ -内啡肽（pp¿EP）或大鼠抗炎基因白细胞介素-10（rIL10/F129S）的突变形式在大鼠慢性神经性疼痛模型中导致症状显着（p<0.0001）缓解3个月，该应用的一个重要功能结果是，通过 LP 的 sc-rAAV8 是一种可行的基因递送产品，可供专业研究中心之外的群体使用。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. 测试该方法在新大鼠中的镇痛功效。反映无法治愈的癌症患者疼痛的模型，这是未来可能的临床试验场景目标 4. 测试 IT sc-rAAV8 是否能有效转导大型动物的 DRG 神经元意义和未来前景：慢性疼痛影响 5000 万美国人，并产生费用。仅在美国每年就花费超过 1000 亿美元（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，该方法将成为候选方法。 IT sc-rAAV8 可用于晚期恶性肿瘤严重疼痛患者的临床开发，可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，也可能成为治疗其他棘手疾病的新药。慢性疼痛。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），脊髓穿刺是向神经系统提供新疗法的一种有吸引力的途径。原因是脊髓起着“疼痛之门”的作用，能够打开以促进疼痛信号传递或“关闭”以控制疼痛。 ;在床边进行；并获得 FDA 批准的常规药物。我们开发了一种通过脊髓穿刺施用新基因载体的基因治疗方法，可以控制疼痛。具体来说，我们在大鼠模型中发现了一种严重的慢性神经性疼痛。通过我们的方法可以控制> 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开发用于人类的可行治疗方法。晚期癌症引起的剧烈疼痛。