Hurler's syndrome is caused by an inherited deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). Deficiency of this enzyme can cause accumulation of undigested substrates in the lysosomes and give rise to severe clinical manifestations. Even though allogeneic bone marrow transplantation (BMT) has been applied as a potential treatment, gene therapy, inserting a therapeutic gene into patient's autologous bone marrow cells, may provide similar benefits without causing immunological complications. In this proposed study, IDUA gene transfer into long-lived pluripotent hematopoietic stem cells using retroviral vectors and IDUA gene expression in mature hematopoietic cells will be examined. Possible enzyme delivery into the central nervous system via microglia cells derived from transduced bone marrow will also be analyzed in long-term reconstituted mice. Furthermore, potential immune responses generated in mice transduced by retroviruses carrying human IDUA will be evaluated. This will help to elucidate the possible mechanisms involved in eliminating or silencing cells expressing foreign protein. Information derived from this study will be important for bone marrow gene therapy of Hurler disease and may eventually lead to developing a gene therapy clinical trial protocol for patients.
| Huang, M M; Tsuboi, S; Wong, A et al. (2000) Expression of human Wiskott-Aldrich syndrome protein in patients' cells leads to partial correction of a phenotypic abnormality of cell surface glycoproteins. Gene Ther 7:314-20 |
| Huang, M M; Wong, A; Yu, X et al. (1997) Retrovirus-mediated transfer of the human alpha-L-iduronidase cDNA into human hematopoietic progenitor cells leads to correction in trans of Hurler fibroblasts. Gene Ther 4:1150-9 |
