Convection perfusion of glucocerebrosidase for neuronopathic Gaucher's disease.

Systemic enzyme replacement for Gaucher's disease has not prevented premature death or severe morbidity in patients with a neuronopathic phenotype, because the enzyme does not cross the blood-brain barrier. We used convection-enhanced delivery for regional distribution of glucocerebrosidase in rat and primate brains and examined its safety and feasibility for neuronopathic Gaucher's disease. Rats underwent intrastriatal infusion and were observed and then sacrificed at 14 hours, 4 days, or 6 weeks. Primates underwent serial magnetic resonance imaging during enzyme perfusion of the right frontal lobe or brainstem, were observed and then sacrificed after infusion completion. Animals underwent histologic and enzymatic tissue analyses. Magnetic resonance imaging revealed perfusion of the primate right frontal lobe or pons with infusate. Enzyme activity was substantially and significantly (p < 0.05) increased in cortex and white matter of the infused frontal lobe and pons compared to control. Immunohistochemistry demonstrated intraneuronal glucocerebrosidase. There was no toxicity. Convection-enhanced delivery can be used to safely perfuse large regions of the brain and brainstem with therapeutic levels of glucocerebrosidase. Patients with neuronopathic Gaucher's disease and similar central nervous system disorders may benefit from this treatment.