权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8333412
负责人：
Zarife Sahenk
金额：
$ 83.86万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8333412
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

项目摘要

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）：本提案的前提是AAV1介导的神经营养因子3 （NT-3）的基因传递将为最常见的遗传性神经病变1A型charot - marie - tooth神经病（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）的存活和分化，促进神经再生。在之前的研究中，外源性给药NT-3增强了CMT， TremblerJ （TrJ）动物模型以及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使用。携带NT-3基因的rAAV1在骨骼肌注射后提供持续有效的神经营养因子来源代表了另一种方法。使用这种方法的初步数据显示，在TrJ中有希望的发现，显示出握力和神经再生的改善。该提案为获得IND以安全交付rAAV1提供了框架。NT-3在CMT1A的1期基因治疗临床试验中。这一目标可以通过两个途径实现。AIM 1使用自互补的AAV和采用肌肉特异性启动子来提高安全性，提供了降低剂量要求的潜力。提出了一个两步范式，将首先比较rAAV1。NT-3在CMV启动子与肌肉特异性截断肌酸激酶（tMCK）启动子的控制下，均以高剂量（1X 1011vg）给予。为了使实验设计的效率最大化，只有达到提高握力的里程碑（成功标准）的启动子将被推进到步骤2。如果tMCK启动子成功，将在低剂量的rAAV1.tMCK下进行测试。NT-3在1 × 1010vg。第二步需要改善复合肌肉动作电位振幅或面积，这一发现与肌肉力量有关。如果仅用巨细胞病毒启动子就能取得成功，那么考虑到治疗这种疾病的需要，仍有很强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IND前会议在内的步骤，将最有希望的载体转移到IND，然后向包括RAC， IRB， IBC在内的所有监管机构提交，完成毒理学/生物分布研究。从该项目获得的信息将允许我们为CMT1A的I期安全性试验提交IND。