Enzyme replacement therapy has been used successfully in many
lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused
enzyme to cross the blood-brain barrier (BBB). We recently reported that
PerT-GUS, a form of β-
glucuronidase (GUS) chemically modified to eliminate its uptake and clearance by
carbohydrate-dependent receptors, crossed the BBB and cleared neuronal storage in an immunotolerant model of murine
mucopolysaccharidosis (MPS) type VII. In this respect, the chemically modified
enzyme was superior to native β-
glucuronidase. Chemically modified
enzyme was also delivered more effectively to heart, kidney, and muscle. However, liver and spleen, which express high levels of
carbohydrate receptors, received nearly fourfold lower levels of
PerT-GUS compared with native GUS. A recent report on PerT-treated
sulfamidase in murine
MPS IIIA confirmed enhanced delivery to other tissues but failed to observe clearance of storage in neurons. To confirm and extend our original observations, we compared the efficacy of 12 weekly i.v. infusions of
PerT-GUS versus native GUS on (i) delivery of
enzyme to brain; (ii) improvement in histopathology; and (iii) correction of secondary elevations of other lysosomal
enzymes. Such correction is a recognized
biomarker for correction of neuronal storage.
PerT-GUS was superior to native GUS in all three categories. These results provide additional evidence that long-circulating
enzyme, chemically modified to escape
carbohydrate-mediated clearance, may offer advantages in treating MPS VII. The relevance of this approach to treat other
lysosomal storage diseases that affect brain awaits confirmation.