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

Prukop, T., Wernick, S., Boussicault, L., Ewers, D., Jäger, K., Adam, J., et al. (2020). Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats. Journal of Neuroscience Research, 98(10), 1933-1952. doi:10.1002/jnr.24679.

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Prukop, T.1, Author           
Wernick, S.1, Author           
Boussicault, L., Author
Ewers, D.1, Author           
Jäger, K., Author
Adam, J.1, Author           
Winter, L.1, Author           
Quintes, S.1, Author           
Linhoff, L.1, Author           
Barrantes‐Freer, A., Author
Bartl, M., Author
Czesnik, D., Author
Zschüntzsch, J., Author
Schmidt, J., Author
Primas, G., Author
Laffaire, J., Author
Rinaudo, P., Author
Brureau, A., Author
Nabirotchkin, S., Author
Schwab, M. H.1, Author           
Nave, K.-A.1, Author           Hajj, R., AuthorCohen, D., AuthorSereda, M. W.1, Author            more..
Affiliations:
1Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173664              

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Free keywords: Charcot-Marie-Tooth; PXT3003; RRID:AB_10572253; RRID:AB_10746275; RRID:AB_1157897; RRID:AB_1556321; RRID:AB_2147165; RRID:AB_2266724; RRID:AB_2564642; RRID:AB_477272; myelination; neuromuscular; therapy.
 Abstract: 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.

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 Dates: 2020-05-312020-06-262020-10
 Publication Status: Published in print
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1002/jnr.24679
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Project name : This study was funded by Pharnext; MWS held a DFG Heisenberg Professorship (SE 1944/1-1) and 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, TP, and KAN were supported by the European Leukodystrophie Society (ELA 2014-020I1). KAN is supported by the DFG (SPP1757 and CNMPB) and holds an ERC Advanced Grant. JZ, JS, and MWS are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO- NMD).
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Funding organization : -
Project name : MyeliNANO
Grant ID : 671048
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Journal of Neuroscience Research
Source Genre: Journal
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Pages: - Volume / Issue: 98 (10) Sequence Number: - Start / End Page: 1933 - 1952 Identifier: ISSN: 0360-4012
ISSN: 1097-4547