Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Charcot–Marie–Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low‐dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co‐culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003‐treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003‐treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003‐treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination. Baclofen, naltrexone and sorbitol synergistically contribute to PXT3003 effects on myelination in Pmp22 transgenic DRG co‐cultures (a) and motor phenotype in CMT1A rats (b). Recovery of neuromuscular junction innervation (c) plays a decisive role in the preservation of fast‐contracting motor fibers (d) which is uncoupled from dysmyelination in CMT1A rats.