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752 ENZYME REPLACEMENT IN FELINE GM2 GANGLIOSIDOSIS: CATABOLIC EFFECTS OF HUMAN β-HEXOSAMINIDASE A (HEX A)

To assess the feasibility of enzyme therapy in human Gm2 gangliosidosis, hampered by hepatic uptake of, and blood-brain barrier (BBB) impermeability to exogenous Hex A, kittens with Gm2 gangliosidosis (a model for human Sandhoff disease) were injected IV or intracarotid (IC) with ∼5 mg purified human placental Hex A. Hepatic uptake was reduced with IV mannan; reversible BBB permeability compatible with survival without gross neurologic sequelae was induced by 1 ml oxygen IC. At 12 to 72 hrs, residual exogenous enzyme activity in liver, spleen, kidney and brain cortex was 100-50%, 14-5%, 22-5% and 50-10%, respectively, of normal endogenous activity. TLC quantitation showed time-and dose-dependent reduction of liver GL4 globoside and Gm2 ganglioside to 20% of affected controls, and increase of Gm3 ganglioside. A reduction of GL4 globoside to 65% of controls was observed in spleen and kidney. These results demonstrate for the first time a catabolic effect of Hex A in vivo at organ level, even at the relatively low extrahepatic levels obtained by hepatic uptake depression. Although oxygen-induced BBB permeability allowed delivery of comparable enzyme activity to the CNS, no effects on Gm2- or Gm3 ganglioside were evident in brain. Higher enzyme doses, longer exposure, and clarification of neuronal uptake specificity are needed to assess catabolic effects in CNS, a prerequisite for therapeutic attempts in humans.