Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer's Disease.

BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.

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.

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.