Delivery of hexosaminidase A to the cerebrum after osmotic modification of the blood--brain barrier.

Publisher Website
Google Scholar
Abstract
A study was undertaken to evaluate the possibility that hexosaminidase A, the enzyme deficient in Tay-Sachs disease, could be effectively delivered to brain. Hypertonic mannitol can be used to osmotically produce reversible disruption of the blood-brain barrier in animals and man without significant neurotoxicity, and such barrier modification significantly increases the delivery of cytoreductive chemotherapy agents to selected areas of brain. By using the rat model of blood-brain barrier modification and radiolabeled enzyme, increased hexosaminidase A delivery to brain was demonstrated in > 85 animals. Time of injection of hexosaminidase A after blood-brain barrier disruption is critical for maximum delivery. Rapid (> 30 s) intra-arterial administration of hexosaminidase A immediately after blood-brain barrier disruption resulted in a marked increase in enzyme delivery to the brain when compared with controls without prior barrier disruption. When the enzyme was administered 15-20 min after barrier disruption, .apprxeq. 50% less hexosaminidase A was delivered; when given 60-120 min after barrier modification, the amount delivered was the same as in control animals. This critical time course differs from that seen in trials of low MW chemotherapeutic agents (methotrexate and adriamycin). Hexosaminidase A may be delivered to the brain by blood-brain barrier modification and may indicate the potential for enzyme replacement in patients who have Tay-Sachs disease.