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

Autor: Yannick Pereira, Julien Laffaire, Gwenaël Primas, Emmanuel Vial, Jonas Mandel, Serguei Nabirotchkin, Aude Milet, Esther Graudens, Mickaël Guedj, Fabrice Glibert, Ilya Chumakov, Julie Foucquier, Michael W. Sereda, Daniel Cohen, Nathalie Cholet, Klaus-Armin Nave, Aurélie Boucard, Rodolphe Hajj, Viviane Bertrand
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Male
Baclofen
Pharmacology
Nerve Fibers
Myelinated
Rats
Sprague-Dawley
Myelin
Mice
0302 clinical medicine
Charcot-Marie-Tooth Disease
Medicine
Sorbitol
Genetics(clinical)
Pharmacology (medical)
Genetics (clinical)
Medicine(all)
0303 health sciences
Systems Biology
General Medicine
Naltrexone
3. Good health
Synergy
medicine.anatomical_structure
CMT1A
Drug Therapy
Combination
Female
Cellular model
Rats
Transgenic
Repurposing
Myelin Proteins
Combination therapy
Transgene
Down-Regulation
Neuroprotection
03 medical and health sciences
In vivo
Animals
Remyelination
030304 developmental biology
business.industry
Regeneration (biology)
Research
Drug Repositioning
Axons
Coculture Techniques
Rats
Disease Models
Animal
Low dose
nervous system
Sorbitol
Synergy
Gene Expression Regulation
Sciatic Neuropathy
business
030217 neurology & neurosurgery
Zdroj: Orphanet Journal of Rare Diseases
ISSN: 1750-1172
Popis: 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. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0201-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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