Autolysosomal enhancer GHF201 attenuates pathophysiology in a mucopolysaccharidosis type I mouse model.

Mucopolysaccharidosis type I (MPS-I) is a hereditary lysosomal storage disorder caused by deficiency in the lysosomal enzyme α-L-iduronidase (IDUA) leading to pathogenic over-accumulation of glycosaminoglycans (GAGs), major constituent of connective tissue and mediators of cell signaling. We tested the therapeutic efficacy of the autolysosomal activator GHF201 in the Idua -/- mouse model of MPS-I. We show that GHF201 reduced GAGs and increased cathepsin activity in Idua -/- mouse embryonic fibroblasts (MEFs) and brain cells. In vivo GHF201 improved aberrant locomotion and behavior, reduced interstitial cathepsins in joints and liver, increased systemic catabolism, corrected bone dysplasia, increased autophagic flux, and ameliorated CNS neurodegeneration and neuroinflammation. GHF201 also reduced brain N-glycans, which are degraded in lysosomes. In conclusion, the lysosomal and autophagic activator GHF201 was demonstrated to improve various pathophysiological parameters in MPS-I-modeling Idua -/- female mice. Our results suggest that GHF201 can complement the inadequate Aldurazyme enzyme replacement therapy as an add-on therapy.