Gene transfer of low levels of β-glucuronidase corrects hepatic lysosomal storage in a large animal model of mucopolysaccharidosis VII

Gene therapy has been at least partially effective in several mouse disease models, but treatment of large mammals has been more difficult to achieve. One major limitation is that only low levels of expression of the corrective gene are often maintained in vivo. In a mouse model of the lysosomal storage disease mucopolysaccharidosis (M PS) type VII (Sly disease) with a null mutation in β-glucuronidase, gene transfer experiments have shown that only 1-2% of normal β-glucuronidase can correct the storage in some major organs. In contrast, M PS VII dogs, cats, and humans that have residual β-glucuronidase activity levels in this range are affected. Thus, higher levels of transferred gene expression may be needed to achieve a therapeutic effect in large animals and humans. We tested this by examining liver pathology in M PS VII dogs after intraperitoneal transplantation of neo-organs containing retrovirus vector-corrected autologous fibroblasts that expressed low levels of β-glucuronidase. The enzyme secreted from the neo-organs was taken up by the liver and significantly reduced the substrate content compared with untreated dogs. This suggests that small amounts of normal enzyme, when delivered to target tissues, may be therapeutically effective in human M PS VII patients.