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: 8132939
• 负责人: Zarife Sahenk
• 金额: $ 35.33万
• 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/8132939
• 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; Cytomegalovirus; Data; Dependovirus; Disease; Dose; Evaluation Research; Experimental Designs; Gene Delivery; Gene Expression; Gene Transfer; Genes; Goals; Half-Life; Hand; Injection of therapeutic agent; Institutional Review Boards; Intramuscular Injections; Investigational Drugs; Investigational New Drug Application; Mediating; Mus; Muscle; Mutation; Nerve Regeneration; Neuropathy; Neurotrophin 3; Outcome Measure; Patients; Peptides; Peripheral Nerves; Phase; Phase I Clinical Trials; Principal Investigator; Recombinant DNA; 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(申请人提供)：这项建议的前提是AAV1介导的神经营养素3(NT-3)基因传递将在临床上改善最常见的遗传性神经病--夏科-玛丽-牙齿神经病1A型(CMT1A)。NT-3是一种重要的自分泌因子，支持雪旺细胞(Schwann cell，SC)存活和分化，促进神经再生。在先前的研究中，在CMT，TremblerJ(TRJ)的动物模型中，外源性给予NT-3促进了神经再生，以及在CMT1A患者中。然而，NT-3较短的血清半衰期限制了其作为治疗性多肽的应用。携带NT-3基因的rAAV1在骨骼肌注射后为这种神经营养因子提供持续有效的来源是一种替代方法。使用这种方法的初步数据在TRJ中显示了令人振奋的发现，表明握力和神经再生得到了改善。这项建议为在CMT1A的1期基因治疗临床试验中获得安全传递rAAV1.NT-3的IND提供了框架。这一目标可以通过两个目标来实现。AIM 1使用自身互补的AAV和使用肌肉特异性启动子来增强安全性，从而提供了降低剂量要求的可能性。提出了一个两步范式，首先比较CMV启动子控制下的rAAV1.NT-3和肌肉特异性截断肌酸激酶(TMCK)启动子，两者都是在高剂量(1×1011 VG)下给予的。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(成功的标准)的启动子将继续进行步骤2。如果tMCK启动子成功，将在1×1010 Vg的低剂量rAAV1.tMCK.NT-3下进行测试。第二步需要改善复合肌肉动作电位的幅度或面积，这一发现与肌肉力量有关。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，仍然有很强的理由将其推进到临床试验。在最终目标(目标2)中，我们将通过包括IND前会议在内的步骤将最有希望的载体转移到IND，然后在完成毒理学/生物分布研究后向包括RAC、IRB、IBC在内的所有监管机构提交报告。从这个项目获得的信息将允许我们提交一份IND，用于CMT1A的第一阶段安全试验。 公共卫生相关性：Charcot-Marie-Tooth神经病是一种常见的疾病，具有严重的残疾，无法治疗。初步的实验和临床资料表明，神经营养因子NT-3可以改善神经病变。本文提出的研究旨在将腺相关病毒(AAV1.NT-3)携带的NT-3应用于CMT1A的1期基因治疗临床试验。这一第一步是获得IND，本提案描述了实现这一目标所需的研究。