SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies
Résumé
Sulfatases are enzymes that hydrolyze a diverse range of sulfate esters. Deficiency of lysosomal sulfatases leads to human diseases characterized by the accumulation of either glycosaminoglycans (GAGs) or sulfolipids. The catalytic activity of sulfatases resides in a unique formylglycine residue in their active site generated by the post-translational modification of a highly conserved cysteine residue. This modification is performed by SUMF1 (Sulfatase Modifying Factor 1) which is an essential factor for sulfatase activities. Mutations in the SUMF1 gene cause Multiple Sulfatase Deficiency (MSD), an autosomal recessive disease in which the activities of all sulfatases are profoundly reduced. In previous studies we showed that SUMF1 has an enhancing effect on sulfatase activity when co-expressed with sulfatase genes in Cos7 cells. Here we demonstrate that SUMF1 displays an enhancing effect on sulfatases activity when co-delivered with a sulfatase cDNA via adeno-associated (AAV)- and lenti (LV)-viral vectors in cells from individuals affected by five different diseases due to sulfatase deficiencies or from murine models of the same diseases (i.e. MLD, CDPX, MPSII, MPSIIIA and MPSVI). The SUMF1 enhancing effect on sulfatase activity resulted in an improved clearance of the intracellular GAG or sulfolipid accumulation. Moreover, we demonstrate that the SUMF1 enhancing effect is also present in vivo after AAV-mediated delivery of the sulfamidase gene to the muscle of MPSIIIA mice, resulting in a more efficient rescue of the phenotype. These results indicate that co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...