Zoledronic acid ameliorates multiple organ pathologies in a murine model of mucolipidosis II by partially restoring mannose-6-phosphate-mediated lysosomal hydrolase activities.

Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.