Background: Xenografts from patients with Charcot-Marie-Tooth type 1A (CMT1A) have shown delayed myelination and impaired regeneration of nude mice axons passing through the grafted segments. Neurotrophin-3 (NT-3), an important component of the Schwann cell (SC) autocrine survival loop, could correct these deficiencies. Objective: To assess the efficacy of NT-3 treatment in preclinical studies using animal models of CMT1A and to conduct a double-blind, placebo-controlled, randomized, pilot clinical study to assess the efficacy of subcutaneously administered NT-3 in patients with CMT1A. Methods: Nude mice harboring CMT1A xenografts and TremblerJ mice with a peripheral myelin protein 22-point mutation were treated with NT-3, and the myelinated fiber (MF) and SC numbers were quantitated. Eight patients received either placebo (n = 4) or 150 μg/kg NT-3 (n = 4) three times a week for 6 months. MF regeneration in sural nerve biopsies before and after treatment served as the primary outcome measure. Additional endpoint measures included the Mayo Clinic Neuropathy Impairment Score (NIS), electrophysiologic measurements, quantitative muscle testing, and pegboard performance. Results: The NT-3 treatment augmented axonal regeneration in both animal models. For CMT1A patients, changes in the NT-3 group were different from those observed in the placebo group for the mean number of small MFs within regeneration units (p=0.0001), solitary MFs, (p=0.0002), and NIS (p= 0.0041). Significant improvements in these variables were detected in the NT-3 group but not in the placebo group. Pegboard performance was significantly worsened in the placebo group. NT-3 was well tolerated. Conclusion: Neurotrophin-3 augments nerve regeneration in animal models for CMT1A and may benefit patients clinically, but these results need further confirmation. Background: Xenografts from patients with Charcot-Marie-Tooth type 1A (CMT1A) have shown delayed myelination and impaired regeneration of nude mice axons passing through the grafted segments. Neurotrophin-3 (NT-3), an important component of the Schwann cell Objective: To assess the efficacy of NT-3 treatment in preclinical studies using animal models of CMT1A and to conduct a double-blind, placebo-controlled, randomized, pilot clinical study to assess the efficacy of subcutaneously administered NT-3 in patients with CMT1A. Methods: Nude mice harboring CMT1A xenografts and TremblerJ mice with a peripheral myelin protein 22-point mutation were treated with NT-3, and the myelinated fibers (MF) and SC numbers were quantitated Eight patients received either placebo (n = 4) or 150 μg / kg NT-3 (n = 4) three times a week for 6 months. MF regeneration in sural nerve biopsies before and after treatment served the the primary outcome measure. Additional endpoint measures included the Mayo Clinic Neuropathy Impairment Score (NIS), electrophysiologic measurements, quantitative muscle testing, and pegboard performance. Results: The NT-3 treatment augmented axonal regeneration in both animal models. For CMT1A patients, changes in the NT -3 group were different from those observed in the placebo group for the mean number of small MFs within regeneration units (p = 0.0001), solitary MFs, (p = 0.0002), and NIS (p = 0.0041). Significant improvements in these variables 3 were well tolerated. Conclusion: Neurotrophin-3 augments nerve regeneration in animal models for CMT1A and may benefit patients clinically , but these results need further confirmation.