NT-3 Results finally published! NT-3 promotes nerve regeneration in CMT1A

[Guest guest]

(NOTE: Most of us here already know about the status of NT-3, as we

have followed this for 4-5 years now. But, the paper has finally been

published! The Abstract is below. ~ Gretchen)

Neurology. 2005 Jul 6

NT-3 promotes nerve regeneration and sensory improvement in CMT1A

mouse models and in patients.

Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum

JM, Mendell JR.

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.

Abstract-- 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 microg/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.