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：
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
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/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

项目摘要

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）是为神经系统提供新颖疗法的有吸引力的途径因为病人安全；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无效。尚未符合安全原则；并有未能靶向神经元。我们已经开发了高效的基因转移到主要感觉通过LP，即胸膜内（IT）的背根神经节神经元（DRG）的神经元重组腺相关病毒血清型8（SC-RAAV8）。 SC-RAAV8的单一管理表达镇痛基因prepro-�-内啡肽（pp¿ep）或大鼠抗的突变形式炎症基因白介素10（RIL10/F129S）导致症状的高度显着缓解（P <0.0001）在大鼠慢性神经性疼痛模型中，E3月是一个重要的功能结果。该应用的假设是通过LP通过LP的SC-RAAV8是可行的基因递送产品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，我们提出以下具体目的：目的1。要在封闭式与打开IT空间中通过立体原理量化DRG传输血清学对IT载体的免疫力，并确定器官分布。目标2。确定在神经性疼痛模型中强的候选治疗基因，并定义是否存在传统疼痛治疗的药理协同作用。目标3。测试抗伤害感受器该方法在新的大鼠模型中的功效，反映了无法治愈的癌症患者的疼痛，A 可能的未来临床试验策略。目标4。测试它是否有效地翻译DRG是否有效地转换大动物中的神经元。意义与未来的观点：慢性疼痛影响5000万美国人仅在美国，就会征收> 1000亿美元/年的成本（如PA-07-282所述）。此应用程序提案一种基因疗法方法，如果研究计划成功，该方法将成为候选人用于晚期恶性肿瘤严重疼痛患者的临床发育。 IT SC-RAAV8 5月用作机理验证试验的工具，例如验证小胶质激活作为治疗靶标在人类中，并且也可能成为其他棘手的慢性疼痛的新药。项目叙述慢性疼痛会影响5000万美国人，仅在美国就造成> 1000亿美元的成本（如前所述）在PA-07-282中）。脊髓水龙头是为神经系统提供新颖疗法的有吸引力的途径多种疾病，尤其是疼痛。原因是脊髓作为疼痛门的作用宽阔，从而促进疼痛信号转移或关闭，从而控制疼痛。脊柱水龙头是患者安全；在床边表演；和FDA批准用于常规药物。我们已经开发了通过控制疼痛的脊柱水龙头来管理新基因载体的基因治疗方法。具体来说，我们发现大鼠模型，一种严重的疼痛类型，慢性神经性疼痛可以通过我们的3个月来控制3个月方法。在本应用程序提出的研究中，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特别关注晚期癌症的严重疼痛。