Gene therapy to promote regeneration in Charcot-Marie-Tooth disease.

The molecular pathogenesis underlying Charcot-Marie-Tooth (CMT) neuropathy subtypes is becoming increasingly variable and identification of common approaches for treatment, independently of the disease causing gene defect, is therefore much desirable. Gene therapy approach from the clinical translational view point is particularly challenging for the most common "demyelinating" CMT1 subtypes, caused by primary Schwann cell genetic defects. Studies have shown that impaired regenerative capacity of distal axons is major contributing factor to distal axonal loss in primary Schwann cell genetic defects and neurotrophin 3 (NT-3) improves impaired regeneration in CMT1 mouse models. This review surveys the evidence supporting the rationale for AAV1.NT-3 surrogate gene therapy to improve nerve regeneration in CMT1A. The translational process, from proof of principal studies to the design of the phase I/IIa trial evaluating scAAV1.tMCK.NTF3 gene therapy for treatment of CMT1A is summarized.