title: Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy.
abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models. We thus hypothesized that a polytherapeutic approach using several drugs, previously approved for other diseases, could be beneficial by simultaneously targeting PMP22 and pathways important for myelination and axonal integrity. A combination of drugs for CMT1A polytherapy was chosen from a group of authorised drugs for unrelated diseases using a systems biology approach, followed by pharmacological safety considerations. Testing and proof of synergism of these drugs were performed in a co-culture model of DRG neurons and Schwann cells derived from a Pmp22 transgenic rat model of CMT1A. Their ability to lower Pmp22 mRNA in Schwann cells relative to house-keeping genes or to a second myelin transcript (Mpz) was assessed in a clonal cell line expressing these genes. Finally in vivo efficacy of the combination was tested in two models: CMT1A transgenic rats, and mice that recover from a nerve crush injury, a model to assess neuroprotection and regeneration. Combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol, termed PXT3003, improved myelination in the Pmp22 transgenic co-culture cellular model, and moderately down-regulated Pmp22 mRNA expression in Schwannoma cells. In both in vitro systems, the combination of drugs was revealed to possess synergistic effects, which provided the rationale for in vivo clinical testing of rodent models. In Pmp22 transgenic CMT1A rats, PXT3003 down-regulated the Pmp22 to Mpz mRNA ratio, improved myelination of small fibres, increased nerve conduction and ameliorated the clinical phenotype. PXT3003 also improved axonal regeneration and remyelination in the murine nerve crush model. Based on these observations in preclinical models, a clinical trial of PTX3003 in CMT1A, a neglected orphan disease, is warranted. If the efficacy of PTX3003 is confirmed, rational polytherapy based on novel combinations of existing non-toxic drugs with pleiotropic effects may represent a promising approach for rapid drug development.
authors.forename: Ilya
authors.initials: I
authors.lastname: Chumakov
authors.forename: Aude
authors.initials: A
authors.lastname: Milet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cholet
authors.forename: Gwenaël
authors.initials: G
authors.lastname: Primas
authors.forename: Aurélie
authors.initials: A
authors.lastname: Boucard
authors.forename: Yannick
authors.initials: Y
authors.lastname: Pereira
authors.forename: Esther
authors.initials: E
authors.lastname: Graudens
authors.forename: Jonas
authors.initials: J
authors.lastname: Mandel
authors.forename: Julien
authors.initials: J
authors.lastname: Laffaire
authors.forename: Julie
authors.initials: J
authors.lastname: Foucquier
authors.forename: Fabrice
authors.initials: F
authors.lastname: Glibert
authors.forename: Viviane
authors.initials: V
authors.lastname: Bertrand
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vial
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guedj
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Hajj
authors.forename: Serguei
authors.initials: S
authors.lastname: Nabirotchkin
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001418:Baclofen / Q000008:administration & dosage; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D058492:Drug Repositioning / Q000379:methods*; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009271:Naltrexone / Q000008:administration & dosage; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013012:Sorbitol / Q000008:administration & dosage
chemical_list: D009185:Myelin Proteins; C489546:Pmp22 protein, rat; D013012:Sorbitol; D009271:Naltrexone; D001418:Baclofen