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NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients

From the Departments of Neurology (Drs. Sahenk, McCracken, King, Freimer, and Mendell), Pediatrics (Drs. Sahenk and Mendell), and Statistics (Dr. Nagaraja), Ohio State University, Columbus; and Regeneron Pharmaceuticals, Inc. (Dr. Cedarbaum), Tarrytown, NY.

Address correspondence and reprint requests to Dr. Z. Sahenk, Columbus Children’s Research Institute, Molecular Medicine Division, 700 Children’s Drive, Room WA 3024, Columbus, OH 43205; e-mail: Sahenk.1{at}osu.edu

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 Trembler^J 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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 13 issue to find the title link for this article.

Editorial, see page 662

This article was previously published in electronic format as an Expedited E-Pub on July 6, 2005, at www.neurology.org.

Supported by Muscular Dystrophy Association and Neuropathy Association research grants. The statistical part was supported by NIH NCRR grant MO1-RR00034.

Disclosure: Neurotrophin-3 and matching placebo solution were supplied by Regeneron Pharmaceuticals at no cost to the patients or the investigator. J.M. Cedarbaum, MD, is a full-time employee of and shareholder in excess of $10,000 in Regeneron. He participated in the design of the study protocol and assisted in the preparation of relevant regulatory submissions.

Received August 20, 2004. Accepted in final form April 21, 2005.

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