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.