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

描述（由申请人提供）：该提案的前提是，AAV 1介导的神经营养因子3（NT-3）基因递送将在最常见的遗传性神经病（Charcot-Marie-Tooth神经病1A型（CMT 1A））中提供临床改善。NT-3是一种重要的自分泌因子，支持雪旺细胞（SC）的存活和分化，并促进神经再生。在先前的研究中，外源性施用NT-3增强了CMT、TremblerJ（TrJ）的动物模型以及CMT 1A患者中的神经再生。然而，NT-3的短血清半衰期限制了其作为治疗肽的用途。携带NT-3基因的rAAV 1在注射骨骼肌后提供这种神经营养素的持续有效来源代表了一种替代方法。使用这种方法的初步数据表明，在TrJ中有希望的发现，显示出改善的握力和神经再生。该提案为获得IND以在CMT 1A的I期基因治疗临床试验中安全递送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提供了使用自身互补的AAV和采用肌肉特异性启动子以提高安全性的较低剂量需求的潜力。提出了两步范例，其将首先比较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，两者均以高剂量（1X 1011 vg）给予。为了使实验设计的效率最大化，只有达到改善握力的里程碑（成功标准）的促进剂将被带入步骤2。如果tMCK启动子成功，则将在低剂量rAAV1.tMCK.NT-3（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启动子就可以获得成功，考虑到治疗这种疾病的需要，仍然有很强的理由将其进行临床试验。在最终目标（AIM 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，然后向所有监管机构（包括RAC、IRB、IBC）提交，并完成毒理学/生物分布研究。从该项目中获得的信息将允许我们提交一项IND，用于CMT 1A的I期安全性试验。 公共卫生相关性：腓骨肌萎缩神经病是一种常见的疾病，具有严重的残疾，没有治疗。初步的实验和临床数据表明，神经营养素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）递送的NT-3引入CMT 1A的1期基因治疗临床试验。第一步是获得IND，本提案描述了使其成为可能所需的研究。

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.