Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A)

PLoS One. 2019 Jan 16;14(1):e0209752. doi: 10.1371/journal.pone.0209752. eCollection 2019.


The most common type of Charcot-Marie-Tooth disease is caused by a duplication of PMP22 leading to dysmyelination, axonal loss and progressive muscle weakness (CMT1A). Currently, no approved therapy is available for CMT1A patients. A novel polytherapeutic proof-of-principle approach using PXT3003, a low-dose combination of baclofen, naltrexone and sorbitol, slowed disease progression after long-term dosing in adult Pmp22 transgenic rats, a known animal model of CMT1A. Here, we report an early postnatal, short-term treatment with PXT3003 in CMT1A rats that delays disease onset into adulthood. CMT1A rats were treated from postnatal day 6 to 18 with PXT3003. Behavioural, electrophysiological, histological and molecular analyses were performed until 12 weeks of age. Daily oral treatment for approximately 2 weeks ameliorated motor deficits of CMT1A rats reaching wildtype levels. Histologically, PXT3003 corrected the disturbed axon calibre distribution with a shift towards large motor axons. Despite dramatic clinical amelioration, only distal motor latencies were improved and correlated with phenotype performance. On the molecular level, PXT3003 reduced Pmp22 mRNA overexpression and improved the misbalanced downstream PI3K-AKT / MEK-ERK signalling pathway. The improved differentiation status of Schwann cells may have enabled better long-term axonal support function. We conclude that short-term treatment with PXT3003 during early development may partially prevent the clinical and molecular manifestations of CMT1A. Since PXT3003 has a strong safety profile and is currently undergoing a phase III trial in CMT1A patients, our results suggest that PXT3003 therapy may be a bona fide translatable therapy option for children and young adolescent patients suffering from CMT1A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Baclofen / pharmacology*
  • Charcot-Marie-Tooth Disease / drug therapy*
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / metabolism
  • Demyelinating Diseases / pathology
  • Disease Models, Animal
  • Drug Combinations
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Male
  • Muscle Weakness / metabolism
  • Myelin Proteins / drug effects
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism
  • Naltrexone / pharmacology*
  • Neural Conduction
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proof of Concept Study
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Schwann Cells / drug effects
  • Signal Transduction / drug effects
  • Sorbitol / pharmacology*


  • Drug Combinations
  • Myelin Proteins
  • PMP22 protein, human
  • Sorbitol
  • Naltrexone
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • Baclofen

Grant support

MWS was supported by the German Ministry of Education and Research (BMBF, CMT-BIO, FKZ: 01ES0812, CMT-NET, FKZ: 01GM1511C, CMT-NRG, ERA-NET ’ERARE3’, FKZ: 01GM1605). MWS holds a DFG Heisenberg Professorship (SE 1944/1-1). TP was supported by the European Leukodystrophie Society (ELA 2014-020I1 to MWS). KAN is supported by the DFG (SPP1757 and CNMPB) and holds an ERC Advanced Grant. This trial was financially supported by Pharnext who provided support in the form of salaries for authors SN, RH and DC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.