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