NT-3 gene therapy to improve peripheral nerve function induced by genetic defect

NT-3基因疗法改善遗传缺陷引起的周围神经功能

• 批准号: 7988407
• 负责人: Zarife Sahenk
• 金额: $ 34.54万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988407
• 关键词: Action Potentials; Advisory Committees; Agreement; Animal Model; Area; Biodistribution; Biology; CMV promoter; Cell Survival; Charcot-Marie-Tooth Disease; Charge; Clinical; Clinical Data; Clinical Trials; Creatine Kinase; Data; Dependovirus; Disease; Dose; Evaluation Research; Experimental Designs; Gene Delivery; Gene Expression; Gene Transfer; Genes; Goals; Half-Life; Hand; Injection of therapeutic agent; Intramuscular Injections; Investigational Drugs; Investigational New Drug Application; MM form creatine kinase; Mediating; Mus; Muscle; Mutation; Nerve Regeneration; Neuropathy; Neurotrophin 3; Outcome Measure; Patients; Peptides; Peripheral Nerves; Phase; Phase I Clinical Trials; Principal Investigator; Recombinant DNA; Research Ethics Committees; Safety; Schwann Cells; Serum; Skeletal Muscle; Source; Testing; Therapeutic; Toxicology; Viral; autocrine; design; disability; extensor digitorum; gene therapy; gene therapy clinical trial; grasp; hereditary neuropathy; improved; manufacturing process; meetings; muscle strength; neurotrophic factor; primary outcome; promoter; public health relevance; quadriceps muscle; sciatic nerve; success; vector

DESCRIPTION (provided by applicant): The premise for this proposal is that AAV1 mediated gene delivery of neurotrophin 3 (NT-3) will provide clinical improvement in the most common inherited neuropathy, Charcot-Marie-Tooth neuropathy type 1A (CMT1A). NT-3 is an important autocrine factor that supports Schwann cell (SC) survival and differentiation and improves nerve regeneration. In prior studies, exogenously administered NT-3 augmented nerve regeneration in the animal model for CMT, TremblerJ (TrJ), as well as in CMT1A patients. However, short serum half-life of NT-3 limits its use as a therapeutic peptide. rAAV1 carrying the NT-3 gene to provide a continuous and efficacious source of this neurotrophin following injection of skeletal muscle represents an alternative approach. Preliminary data using this approach demonstrates promising findings in the TrJ showing improved grip strength and nerve regeneration. This proposal provides the framework for obtaining an IND to safely delivery a rAAV1.NT-3 in a phase 1 gene therapy clinical trial for CMT1A. This goal can be achieved in two aims. AIM 1 provides the potential for lower dosing requirements using a self-complementary AAV and a employing a muscle specific promoter to enhance safety. A two step paradigm is proposed that will first compare the rAAV1.NT-3 under control of the CMV promoter versus the muscle specific truncated creatine kinase (tMCK) promoter both given at high dose (1X 1011 vg). To maximize efficiency of the experimental design only the promoter reaching the milestone (criteria for success) of improving grip strength will be carried forward to Step 2. If the tMCK promoter is successful it will be tested at low dose, rAAV1.tMCK.NT-3 at 1 X 1010 vg. Step two requires improvement in compound muscle action potential amplitude or area, a finding that correlates with muscle strength. If success can be reached with only the CMV promoter, there is still a strong rationale for carrying this forward to clinical trial considering the need for treatment of this disease. In the final goal (AIM 2) we will move the vector with most promise to an IND through the steps that include a pre-IND meeting, followed by presentation to all of the regulatory bodies including RAC, IRB, IBC, with completion of the toxicology/biodistribution studies. The information derived from this project will permit us to submit an IND for a phase I safety trial in CMT1A. Public Health Relevance: Charcot-Marie-Tooth neuropathies are common disorders with significant disabilities that have no treatment. Preliminary experimental and clinical data indicates that the neuropathy can be improved by neurotrophin, NT-3. The studies proposed here are designed to bring NT-3 delivered by adeno-associated virus (AAV1.NT-3) to a phase 1 gene therapy clinical trial for CMT1A. This initial step is obtaining an IND and this proposal describes the studies necessary to make this possible.

描述（由申请人提供）：该提案的前提是 AAV1 介导的神经营养蛋白 3 (NT-3) 基因递送将为最常见的遗传性神经病、夏科-马里-图思神经病 1A 型 (CMT1A) 提供临床改善。 NT-3 是一种重要的自分泌因子，支持雪旺细胞 (SC) 存活和分化并改善神经再生。在之前的研究中，外源性给予 NT-3 增强了 CMT 动物模型 TremblerJ (TrJ) 以及 CMT1A 患者的神经再生。然而，NT-3 的血清半衰期短限制了其作为治疗肽的用途。携带 NT-3 基因的 rAAV1 在注射骨骼肌后提供这种神经营养素的连续有效来源，代表了另一种方法。使用这种方法的初步数据证明了 TrJ 的有希望的发现，显示出握力和神经再生的改善。该提案为获得 IND 以在 CMT1A 的 1 期基因治疗临床试验中安全地递送 rAAV1.NT-3 提供了框架。这一目标可以通过两个目标来实现。 AIM 1 使用自我互补的 AAV 和使用肌肉特异性启动子来提高安全性，从而提供了降低剂量要求的潜力。提出了一个两步范例，首先将 CMV 启动子控制下的 rAAV1.NT-3 与肌肉特异性截短肌酸激酶 (tMCK) 启动子进行比较，两者均以高剂量 (1X 1011 vg) 给予。为了最大限度地提高实验设计的效率，只有达到提高握力的里程碑（成功标准）的启动子才会进入步骤 2。如果 tMCK 启动子成功，将以低剂量 rAAV1.tMCK.NT-3 在 1 X 1010 vg 下进行测试。第二步需要改善复合肌肉动作电位幅度或面积，这一发现与肌肉力量相关。如果仅用 CMV 启动子就能取得成功，考虑到治疗这种疾病的需要，仍有充分的理由将其推进临床试验。在最终目标（AIM 2）中，我们将通过包括预 IND 会议在内的步骤，将最有希望的载体转移到 IND，然后向所有监管机构（包括 RAC、IRB、IBC）进行介绍，并完成毒理学/生物分布研究。从该项目中获得的信息将使我们能够提交 CMT1A 第一阶段安全试验的 IND。 公共卫生相关性：腓骨肌萎缩症神经病是一种常见疾病，具有严重残疾且无法治疗。初步实验和临床数据表明神经营养蛋白NT-3可以改善神经病变。这里提出的研究旨在将腺相关病毒 (AAV1.NT-3) 传递的 NT-3 引入 CMT1A 的 1 期基因治疗临床试验。第一步是获得 IND，该提案描述了实现这一目标所需的研究。