In vivo delivery of human α-L-iduronidase in mice implanted with neo-organs

Mucopolysaccharidose type I is a lysosomal storage disease caused by a deficiency in the enzyme α L-iduronidase (IDUA). The existence of a secretory pathway for lysosomal enzymes and the capture of secreted molecules by distant cells through binding to mannose-6-phosphate receptors have provided a rationale for enzyme replacement therapy in lysosomal storage diseases. We have used genetically modified fibroblasts implanted into neo-organs as an in vivo delivery system for IDUA. The human IDUA cDNA was isolated and inserted into a retroviral vector where it was expressed from the phosphoglycerate kinase 1 gene promoter. MPS I fibroblasts transduced with this vector showed high levels of IDUA activity and secreted phosphorylated molecules that could be internalized by naive deficient cells. Neo-organs containing 2 x 10⁷ IDUA-secreting cells were implanted into nude mice. Human and murine IDUA activities were measured in the liver I and spleen of animals sacrificed 35-77 days after implantation. Human IDUA activity corresponded to 0.6-2.3% of the murine enzyme activity in the liver and to 0.1-0.3% in the spleen. These data indicated that human IDUA was secreted from neo-organs and internalized in distant tissues.