Pharmacological read‐through of nonsense ARSB mutations as a potential therapeutic approach for mucopolysaccharidosis VI

Rosa Bartolomeo, Elena V. Polishchuk, Nicola Volpi, Roman S. Polishchuk, Alberto Auricchio

Mucopolysaccharidosis type VI (MPS VI) is a severe lysosomal storage disorder without central nervous system involvement caused by arylsulfatase B (ARSB) deficiency. MPS VI is characterized by dysostosis multiplex, corneal clouding, heart valve defects and urinary excretion of glycosaminoglycans (GAGs). The current treatment for MPS VI is enzyme replacement therapy (ERT) which has limited efficacy on bone, joints and heart valve disease, as well as high costs. A potential therapeutic approach for the subgroup of MPS VI patients that carry nonsense mutations is to enhance stop-codon read-through, using small molecules, to restore production of the full-length ARSB protein. In this study we investigated whether two compounds known to induce stop codon read-through, the aminoglycoside gentamicin and PTC124, can promote read-through of four different ARSB nonsense mutations (p.R315X, p.R327X, p.Q456X and p.Q503X) associated with MPS VI and enable the synthesis of full-length functional ARSB protein in patients fibroblast cell lines. Our study demonstrates that PTC124 but not gentamicin, increases the level of ARSB activity in three MPS VI patient fibroblast cell lines. In two of them the levels of ARSB activity obtained were significantly higher than in untreated cells, reaching ≤2.5 % of those detected in wild-type fibroblasts and resulting in significant reduction of lysosomal size. Since even small increases in enzyme activity can dramatically influence the clinical phenotype of MPS VI, our study suggests that pharmacological read-through may be combined with ERT potentially increasing therapeutic efficacy in those patients bearing nonsense ARSB mutations.