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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK009430-02
Application #
2391284
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Hyde, James F
Project Start
1997-04-01
Project End
Budget Start
1997-04-01
Budget End
1997-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Southern California
Department
Genetics
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089