Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice

The lysosomal storage disorders are a large group of inherited diseases tha t involve central nervous system degeneration. The disease in the brain has generally been refractory to treatment, which will require long-term corre ction of lesions dispersed throughout the central nervous system to be effe ctive. A promising approach is somatic gene therapy but the methods have so far been inadequate because they have only achieved short-term or localize d improvements. A potential approach to overcome these limitations is to ob tain sustained high level expression and secretion of the missing normal en zyme from a small group of cells for export to neighboring diseased cells, which might allow the therapeutic protein to reach distal sites. We tested this in a mouse model of mucopolysaccharidosis VII (Sly disease) using an a denoassociated virus vector. After a single treatment the vector continuous ly produced the normal enzyme from infected cells at the injection sites. T he secreted enzyme was disseminated along most of the neuraxis, resulting i n widespread reversal of the hallmark pathology. An extensive sphere of cor rection surrounding the transduction sites was created, suggesting that a l imited number of appropriately spaced sites of gene transfer may provide ov erlapping spheres of enzyme diffusion to cover a large volume of brain tiss ue. (C) 1999 Academic Press.