Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis typeVII mouse

The central nervous system (CNS) is a predominant site of involvement in se veral lysosomal storage diseases (LSDs); and for many patients, these disea ses are diagnosed only after the onset of symptoms related to the progressi ve accumulation of macromolecules within lysosomes, The mucopolysaccharidos is type VII (MPS VII) mice are deficient for the lysosomal enzyme beta-gluc uronidase and, by early adulthood, develop a significant degree of glycosam inoglycan storage within neuronal, glial, and leptomeningeal cells, Using t his animal model, we investigated whether gene transfer mediated by a recom binant adeno-associated virus (rAAV) vector is capable of reversing the pro gression of storage lesions within the CNS, Adult MPS VII mice received int racerebral injections of 4 X 10(7) infectious units of a rAAV vector carryi ng the murine beta-glucuronidase (gus-s(a)) cDNA under the transcriptional direction of the cytomegalovirus immediate-early promoter and enhancer. By 1 month after vector administration, transgene-derived beta-glucuronidase w as present surrounding the injection site. Enzyme levels were between 50 an d 240% of that found in wild-type mice, This level of beta-glucuronidase ac tivity was sufficient to reduce the degree of lysosomal storage. Moreover, the reduction in storage was maintained for at least 3 months post-rAAV adm inistration, These data demonstrate that rAAV vectors can transduce the dis eased CNS of MPS VII mice and mediate levels of transgene expression necess ary for a therapeutic response, Thus, rAAV vectors are potential tools in t he treatment of the mucopolysaccharidoses and other lysosomal storage disea ses.