Arylsulfatase A (ASA)-deficient mice represent an animal model for the fatal
lysosomal storage disease metachromatic leukodystrophy, which is characterized by widespread intralysosomal deposition of
sulfatide. Bone marrow stem cell gene therapy in mice, using a retroviral vector mediating expression of wild-type human ASA, has the potential to ameliorate the visceral pathology, but improves the prevailing
brain disease and
neurologic symptoms only marginally. One factor that influences the efficacy of
bone marrow transplantation therapy in
lysosomal storage diseases is the secretion level of the therapeutic
enzyme from donor-type cells. Here we test the potential of a hypersecreted glycosylation variant of ASA. Although this mutant lacks
mannose 6-phosphate residues it is taken up by cells by a
mannose 6-phosphate receptor-independent pathway and causes partial metabolic correction of ASA-deficient mouse cells. Retrovirally mediated transfer of the mutant
cDNA into ASA-deficient mice results in the sustained expression of the transgene. Serum levels argue for an increased secretion of the glycosylation mutant also in vivo. Tissue levels were reduced to 2% in liver and up to 40% in kidney compared with animals treated with the wild-type
enzyme, indicating reduced endocytosis. Thus, the limited uptake of the variant
enzyme outweighs the putative advantageous effect of improved supply. Although the mutant
enzyme is able to correct the metabolic defect partially, histological examinations did not reveal any reduction of
sulfatide storage in treated animals. Surprisingly, analysis of
neurologic symptoms indicated a significant improvement of the gait pattern.