CMT 1A + NT-3: TrkB and TrkC agonist antibodies improve function, electrophysiol

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Exp Neurol. 2010 May 26

TrkB and TrkC agonist antibodies improve function, electrophysiologic and

pathologic features in trembler(j) mice.

Sahenk Z, Galloway G, C, Malik V, Kaspar BK, Eagle A, Yetter B, Forgie

A, Tsao D, Lin JC.

Research Institute at Nationwide Children's Hospital, The Ohio State University,

Columbus.

Abstract

Neurotrophic factors have been considered as potential therapeutics for

peripheral neuropathies. Previously, we showed that neurotrophin-3 (NT-3)

promotes nerve regeneration in trembler(J) (Tr(J)) mice and in sural nerves from

patients with Charcot-Marie-Tooth 1A (CMT1A).

The relatively short plasma half-life of NT-3 and other neurotrophins, however,

pose a practical difficulty in their clinical application. Therapeutic agonist

antibodies (AAb) targeting the neurotrophic receptors may circumvent this

obstacle due to their high specificity and long half-life.

Using morphological, electrophysiological studies and functional motor testing,

we assessed the efficacy of monoclonal TrkC AAb and TrkB AAb in the Tr(J) mice.

Treatments of these AAbs individually or in combination over 20weeks increased

compound muscle action potential (CMAP) amplitude, which correlated with

improved grip strength, as compared to the PBS-control group. Improvements in

CMAP amplitude were most prominent with TrkC AAb treatment.

In all treatment groups, distal to the crush site of the sciatic nerves

exhibited a significantly greater number of myelinated fibers (MFs) indicating

improved regenerative response to injury. In the contralateral intact sciatic

nerves, the number of MFs as well as the myelin thickness was also increased

significantly by the AAb treatments, suggesting that the

hypomyelination/amyelination state of the peripheral nerves in Tr(J) improved.

Therapeutic response to AAb combination was often, albeit not always, the most

prominent, indicating a non-redundant effect of TrkB and TrkC AAbs. An early

functional recovery and the correlative morphological changes of enhanced

regeneration were seen with TrkC AAb treatment.

These results provide evidence for potential therapeutic use of monoclonal

agonist antibodies for neurotrophin receptors in CMT1A and other neuropathies.