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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Gwinn, Katrina
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Nationwide Children's Hospital
United States
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Sahenk, Zarife; Galloway, Gloria; Clark, Kelly Reed et al. (2014) AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy. Mol Ther 22:511-21