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 m ucopolysaccharide storage disorder resulting from a genetic deficiency of alpha-L-iduronidase (IDUA), which is required for lysosomal degrad ation of glycosaminoglycans heparan sulfate and dermatan sulfate. Even though histocompatible bone marrow transplantation has been applied f or 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 c onstructed using Moloney murine leukemia virus (MoMLV)-based vector ba ckbones. High-titer vector-producing clones containing the L-HuID-SN a nd MFG-HuID retroviral vectors were established. The efficiency of gen e transfer into primitive human CD34(+) hematopoietic cells using both retroviral vectors is in the rage of 18-23%. The level of enzyme expr ession 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 c orrected Hurler fibroblasts via mannose-6-phosphate receptors. These f indings suggest that genetically modified hematopoietic progenitor cel ls can potentially be useful for gene therapy of Hurler syndrome.