The present studies were undertaken to evaluate the possibility that
hexosaminidase A, the
enzyme deficient in
Tay--Sachs disease, could be effectively delivered to brain. Previous studies from our laboratory have shown that hypertonic
mannitol can be used to osmotically produce reversible disruption of the blood--brain barrier in animals (rat and dog) and man without significant neurotoxicity and that 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 has been demonstrated in more than 85 animals. The time of injection of
hexosaminidase A after blood--brain barrier disruption is critical for maximum delivery. Rapid (over 30 sec) 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, approximately 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 is very different than that seen in trials of low molecular weight chemotherapeutic agents (
methotrexate and
adriamycin). These preliminary studies suggest that
hexosaminidase A can be delivered to the brain by blood--brain barrier modification and may be indicative of the potential for
enzyme replacement in patients who hae
Tay--Sachs disease.