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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0201-x) contains supplementary material, which is available to authorized users.

Promoting peripheral myelin repair

“…In a recent systems biology-based approach a novel combination of three repurposed drugs, namely baclofen, naltrexone and sorbitol (named PXT3003) were tested in CMT1A animal models and in a phase 2 clinical trial (Attarian et al, 2014; Chumakov et al, 2014). Prior to the clinical trial, PXT3003 was studied in three distinct experimental models; including myelinating cocultures from CMT1A rats, transgenic PMP22 overproducing rats and in mouse nerve crush injury (Chumakov et al, 2014). In each of these experimental paradigms, the three combined drugs proved efficacies in improving myelination and ameliorating neuropathic phenotype, including lowering PMP22 message levels (Chumakov et al, 2014).…”

“…Prior to the clinical trial, PXT3003 was studied in three distinct experimental models; including myelinating cocultures from CMT1A rats, transgenic PMP22 overproducing rats and in mouse nerve crush injury (Chumakov et al, 2014). In each of these experimental paradigms, the three combined drugs proved efficacies in improving myelination and ameliorating neuropathic phenotype, including lowering PMP22 message levels (Chumakov et al, 2014). Significantly, PXT3003 was shown to be safe, with good tolerability in a one-year long clinical trial with 80 adult CMT1A patients (Attarian et al, 2014).…”

“…Because of the positive results from the Phase II clinical trial (Attarian et al, 2014), Pharnext is launching an international, multi-center, randomized, double blind, placebo-controlled Phase III study with PTX3003. Since PTX3003 was effective in improving myelination in the nerve crush injury model (Chumakov et al, 2014) it is possible that this investigational Pleodrug will be beneficial in both chronic and acute demyelination paradigms.…”

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

“…Further links between CMT and alcohol dependence are provided by recent studies, showing that a triple-therapy with a combination of naltrexone, baclofen, and sorbitol (PXT3003) can improve health of patients suffering from CMT disease. 53,54 While PXT3003 was shown to downregulate PMP22 mRNA expression and improve myelination as well as axonal regeneration, 53 both naltrexone and baclofen are also used (partly off-label) to treat alcohol dependence. 55 Acting as an opioid antagonist (naltrexone) and a GABA-B-receptor agonist (baclofen), respectively, these drugs reduce the rewarding effects of alcohol and inhibit dopaminergic neurotransmission.…”

Pediatric Charcot-Marie-Tooth Disease

“…[94][95][96][97] There is a promising ongoing search for small molecules that can influence the deleterious effects of the misfolded proteins that are responsible for some dominant CMT forms. 98 Gene therapy can be considered for replacing the defective genes responsible for recessive CMT types or to express protective neurotrophic molecules. 99,100 The optimal selective gene delivery system has not yet been discovered.…”