Retrovirus-mediated transfer of the human alpha-L-iduronidase cDNA into human hematopoietic progenitor cells leads to correction in trans of Hurler fibroblasts

Hurler syndrome (mucopolysaccharidosis IH or MPS IH) is a congenital mucopolysaccharide storage disorder resulting from a genetic deficiency of alpha-L-iduronidase (IDUA), which is required for lysosomal degradation of glycosaminoglycans heparan sulfate and dermatan sulfate. Even though histocompatible bone marrow transplantation has been applied for the treatment of Hurler syndrome, gene therapy via autologous bone marrow transplantation (BMT) may be more beneficial for this disease. Two retroviral vectors containing a full-length human IDUA cDNA were constructed using Moloney murine leukemia virus (MoMLV)-based vector backbones. High-titer vector-producing clones containing the L-HuID-SN and MFG-HuID retroviral vectors were established. The efficiency of gene transfer into primitive human CD34(+) hematopoietic cells using both retroviral vectors is in the rage of 18-23%. The level of enzyme expression in transduced primary bone marrow cells was increased 40- to 50-fold compared with that of sham-transduced cells. Enzyme produced by the progeny of the transduced human CD34(+) cells carrying IDUA cDNA corrected Hurler fibroblasts via mannose-6-phosphate receptors. These findings suggest that genetically modified hematopoietic progenitor cells can potentially be useful for gene therapy of Hurler syndrome.