Targeting the mitochondrial enzyme monoamine oxidase B to treat mucopolysaccharidoses: a drug repurposing strategy

Mucopolysaccharidoses (MPSs) are a group of 12 rare pediatric metabolic disorders, each due to the deficit of one of the lysosomal enzymes normally degrading mucopolysaccharides, which therefore pathologically accumulate in the cells of most tissues and organs, determining a severe clinical phenotype. For five types of MPSs a protocol of enzyme replacement therapy (ERT) has been developed, consisting in the weekly intravenous infusion of the functional enzyme. ERT, partially effective in some tissues and organs, remains, however, poorly effective in important body districts, as the cardiac and the osteo-articular ones, and totally ineffective on the neurological impairment, affecting most patients. Abnormal mucopolysaccharide accumulation, a common feature of all MPSs, triggers a general inflammatory status although the mechanisms are only partially known. Inflammation is considered the main cause of neuropathogenesis and osteoarticular disease in MPS. Our project is part of Telethon's mission, as it proposes a low-cost strategy, called 'drug repurposing' (repurposing of a known drug for a new therapeutic target), that is particularly interesting for rare diseases for which investments are often limited. On the basis of promising preliminary data and scientific background, we will evaluate the efficacy of a drug, clinically approved for years to treat Parkinson's disease, in mouse models of MPS II and MPS IIIB (through biochemical, histological and behavioral analyses) and in cells from MPS II and MPS IIIB patients. This drug also has the advantage of reaching the brain and heart, and of being easily administered orally.