Expression and secretion of human glucocerebrosidase mediated by recombinant lentivirus vectors in vitro and in vivo: implications for gene therapy of Gaucher disease.

Gaucher disease is a lysosomal storage disorder resulting from a deficiency of glucocerebrosidase (GC). In this study, we showed that vascular and hepatic delivery of a HIV-1-based lentivirus vector encoding human GC cDNA produced therapeutic levels of GC protein. A high level of expression of GC was produced in cultured fibroblasts derived from patients with Gaucher disease by transducing the cells with recombinant lentivirus vectors. GC secreted by transduced fibroblasts was taken up by adjacent GC-deficient cells by endocytosis. Intraportal administration of lenti-EF-GC viral vector resulted in efficient transduction and expression of the GC. Vascular delivery of vector resulted in high levels of GC expression in mice that persisted in most organs over the four months. No significant abnormalities were found attributable to recombinant lentivirus vectors in any of the tissues examined. This study represents an initial step toward gene transfer using recombinant lentivirus vectors for treatment of Gaucher disease.