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Multiple Acyl-CoA Dehydrogenases Deficiency (MADD): a preclinical animal model and a rational approach for drug design targeting mitochondrial metabolism

21st national competition for scientific and technical research

Rare diseases

Senior Researcher : Laura Formentini

Research Centre or Institution : Fundación Severo Ochoa, CBM

Abstract

Mutations in the ETFDH gene generate the Multiple Acyl-CoA Dehydrogenase Deficiency (MADD; OMIM #231680), an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. MADD presents a heterogeneous clinical spectrum that includes a severe phenotype of metabolic acidosis, hypoglycemia and hyperammonemia -leading to hypertrophic cardiomyopathy and perinatal death- or the more common presentation of myopathy, exercise intolerance, and metabolic decompensation with episodes of rhabdomyolysis.

Because of the lack of animal models, the pathogenic mechanisms of MADD are only partially understood and nowadays there is no cure for this pathology. We have recently generated the first conditional and skeletal muscle-specific ETFDH-ko mouse, that reproduces several aspects of MADD disease, including increasing lipogenesis, acidosis, the presence of interfiber lipid droplets and shrinkage of fibers. These animals represent a good preclinical model for testing molecules aimed at restoring skeletal muscle and whole body homeostasis.

      Our aim is to characterize the mouse phenotype, identifying new mitochondrial molecular targets and therapies for MADD. This could mean the identification of new molecules able of boosting muscle mitochondria activity or the repurposing of drugs already used in therapy for different indications. Drug repurposing offers a valuable approach to reduce the socio-economic burden of rare diseases: it has emerged as an alternative strategy to overcome the costs and time invested in drug discovery. This approach may lead to new therapies with acceptable known side effects, being able to improve the patient quality of life in a short time.

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