TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in TremblerJ mice

Abstract

Neurotrophic factors have been considered as potential therapeutics for peripheral neuropathies. Previously, we showed that neurotrophin-3 (NT-3) promotes nerve regeneration in TremblerJ (TrJ) 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 TrJ 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 TrJ 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.