Pharmacological chaperones as an alternative to increase GALNS activity in mucopolysaccharidosis type IVA

Although the use of pharmacological chaperones (PCs) has been evaluated as an alternative to assist the folding of mutated enzymes and increase the efficiency of the enzymatic replacement therapy in lysosomal diseases, in mucopolysaccharidosis IVA there are no reports of which GALNS mutations are responsive to chaperones. In this study, three previously identified PCs (bromocriptine, ezetimibe and pranlukast) were used to evaluate their effect in GALNS mutations through enzymatic activity assays in HEK-293 cell extracts. At the same time, the co-administration of PCs and fluorescent labeled elosulfase alfa was used to evaluate possible changes in the pharmacokinetic and bio distribution of the enzyme in a murine model. After evaluation of the most frequently reported mutations for GALNS in Morquio patients, an increase in GALNS activity was observed in cells treated with the following combinations of mutations and PCs: S341R/pranlukast, R90W/ezetimibe and pranlukast. Evaluation of the pharmacokinetic showed a 50% increase in elosulfase alfa activity 4 h after co-administration of bromocriptine compared with the control. In conclusion, as previously hypothesized each PC has a different folding effect over different GALNS mutations. In addition, the use of PCs can be further evaluated as an alternative to enhance the efficiency of the enzymatic replacement therapy.