Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer

Mucopolysaccharidosis VII, a classical lysosomal storage disease, is caused by deficiency of the enzyme beta-glucuronidase. Central nervous system (CN S) manifestations are severe with accumulations of storage vacuoles in all cell types. Intraventricular gene transfer can lead to transduction of the ependyma, with production and secretion of beta-glucuronidase into the cere bral spinal fluid and underlying cortex resulting in reversal of disease pa thology restricted to the periventricular areas. We tested if systemic hype rosmolality would increase the distribution of beta-glucuronidase in brain parenchyma after intraventricular virus injection. Mice were administered m annitol, intraperitoneally, 20 days after gene transfer and 1 day prior to sacrifice. Mannitol-induced systemic hyperosmolality caused a marked penetr ation of beta-glucuronidase into the brain parenchyma. If mannitol was admi nistered at the time of the intraventricular injection of virus, there was penetration of vector across the ependymal cell layer, with infection of ce lls in the subependymal region. This also resulted in increased beta-glucur onidase activity throughout the brain. Sections of brains from beta-glucuro nidase-deficient mice showed correction of cellular pathology in the subepe ndymal region plus cortical structures away from the ventricular wall. Thes e data indicate that virus-mediated gene transfer to the brain via the vent ricles, coupled with systemic mannitol administration, can lead to extensiv e CNS distribution of beta-glucuronidase with concomitant correction of the storage defect. Our findings have positive therapeutic implications for th e treatment of CNS disorders with gene transfer vectors and recombinant pro teins. (C) 1999 Academic Press.