Triclabendazole suppresses cellular levels of glycosaminoglycan-A potential therapeutic agent for mucopolysaccharidoses and related diseases.

Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal recessive inherited disorder of mucopolysaccharide metabolism with a severe clinical course. The causative gene VPS33A regulates membrane trafficking, including autophagy and endocytosis. However, how the patient-specific mutation impacts VPS33A function is unknown. We have contrived an experimental method utilizing flow cytometry to evaluate protein levels required for certain cellular functions, named DEFAC, and concluded that the mutant VPS33A has a comparable function in autophagy to the wild-type at the molecular level. There is no specific treatment for MPSPS that is not due to lysosomal enzyme deficiencies or known VPS33A functions. We screened the FDA-approved drug library and identified triclabendazole as a potential curative for MPSPS. Triclabendazole reduced mucopolysaccharide in MPSPS and Mucopolysaccharidosis model cells and represented therapeutic effects on MPSPS model mice. These results suggest that triclabendazole is a widely applicable therapeutic not only to MPSPS but also to related diseases with mucopolysaccharide accumulation.