GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases, are lysosomal storage disorders characterized by the lysosomal accumulation of GM2
gangliosides. This accumulation is due to deficiency in the activity of the β-
hexosaminidases Hex-A or
Hex-B, which are dimeric
hydrolases formed by αβ or ββ subunits, respectively. These disorders show similar clinical manifestations that range from mild systemic symptoms to neurological damage and premature death. There is still no effective
therapy for
GM2 gangliosidoses, but some therapeutic alternatives, as
enzyme replacement therapy, have being evaluated. Previously, we reported the production of active human recombinant β-
hexosaminidases (rhHex-A and rhHex-B) in the methylotrophic yeast Pichia pastoris. In this study, we evaluated in vitro the cellular uptake, intracellular delivery to lysosome, and reduction of stored substrates. Both
enzymes were taken-up via endocytic pathway mediated by
mannose and
mannose-6-phosphate receptors and delivered to lysosomes. Noteworthy, rhHex-A diminished the levels of stored
lipids and lysosome mass in fibroblasts from Tay-Sachs patients. Overall, these results confirm the potential of P. pastoris as host to produce recombinant β-
hexosaminidases intended to be used in the treatment of
GM2 gangliosidosis.