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 congenital defect of protective protein/cathepsin A, and secondary deficiency of neuraminidase-1 and β–galactosidase. Protective protein/cathepsin A is a lysosomal serine carboxypeptidase that functions as chaperone for neuraminidase-1 and β-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 towards the development of enzyme replacement therapy for galactosialidosis, using a recombinant human protective protein/cathepsin A. We show that the recombinant enzyme, taken up by patient-derived fibroblasts, restored cathepsin A, neuraminidase 1 and β-galactosidase activities. Long-term, bi-weekly injection of the recombinant enzyme in a cohort of PPCA–/– mice, a faithful model of the disease, demonstrated a dose-dependent, systemic internalization of the enzyme by cells of various organs, including the brain, which resulted in restoration/normalization of the three enzyme activities, resolution of histopathology and reduction of sialyloligosacchariduria. These positive results underscore the benefits of a protective protein/cathepsin A-mediated enzyme replacement therapy for the treatment of galactosialidosis.