Galactosialidosis: preclinical enzyme replacement therapy in a mouse model of the disease, a proof of concept

ABSTRACT: Galactosialidosis is a rare lysosomal storage disease caused by a congenital defect of protective protein/cathepsin A (PPCA) and secondary deficiency of neuraminidase-1 and ?-galactosidase. PPCA is a lysosomal serine carboxypeptidase that functions as a chaperone for neuraminidase-1 and ?-galactosidase within a lysosomal multi-protein complex. Combined deficiency of the three enzymes leads to accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids and manifests in a systemic disease pathology with severity mostly correlating with the type of mutation(s) and age of onset of the symptoms. Here, we describe a proof-of-concept, preclinical study toward the development of enzyme replacement therapy for galactosialidosis, using a recombinant human PPCA. We show that the recombinant enzyme, taken up by patient-derived fibroblasts, restored cathepsin A, neuraminidase-1, and ?-galactosidase activities. Long-term, bi-weekly injection of the recombinant enzyme in a cohort of mice with null mutation at the PPCA (CTSA) locus (PPCA–/–), a faithful model of the disease, demonstrated a dose-dependent, systemic internalization of the enzyme by cells of various organs, including the brain. This resulted in restoration/normalization of the three enzyme activities, resolution of histopathology, and reduction of sialyloligosacchariduria. These positive results underscore the benefits of a PPCA-mediated enzyme replacement therapy for the treatment of galactosialidosis. Graphical Abstract d’Azzo et al. describe the development of enzyme replacement therapy for the treatment of galactosialidosis, a lysosomal storage disease caused by a primary defect of the lysosomal protective protein/cathepsin A and secondary deficiency of neuraminidase-1 and ?-galactosidase. Galactosialidosis is one of the orphan diseases for which there is no cure.

SUBMITTER: Cadaoas J 

PROVIDER: S-EPMC7782203 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature