Recessive mutations in FOXP3, a new immune-modulating gene, cause a rare, infantile form of immune-mediated insulin-dependent diabetes mellitus (IDDM) in human males, IPEX. IPEX has been cured by a bone marrow transplant resulting in only 16 percent donor cells, suggesting that normal cells can suppress the abnormally reactive recipient T cells. We think that IPEX might also be cured by gene therapy with FOXP3, since only a fraction of hematopoietic cells with the normal gene are needed to correct the disease. A natural mutant mouse strain, scurfy (sf), has features that recapitulate much of IPEX, including early death. Scurfy mice have a mutation in Foxp3, the mouse ortholog of FOXP3. Scurfy is the true genetic equivalent of human IPEX and is thus a useful model in which to study the human disease and in which to test novel treatment strategies. The X-linked genetic susceptibility locus for common, Juvenile Onset (Type 1) Diabetes Mellitus (JODM), IDDM-X, and FOXP3 map to the same chromosome location. We hypothesize that FOXP3 is the susceptibility gene for JODM, and that biologically significant variations in the gene or in its regulatory DNA predispose to autoimmunity. In this study, we propose to treat scurfy mice with Foxp3 gene therapy using retroviral vectors, and to test for an association between gene sequence variations in human FOXP3 and susceptibility to JODM. If both are successful, FOXP3 gene therapy for JODM could be envisioned.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK060207-01
Application #
6400200
Study Section
Special Emphasis Panel (ZDK1-GRB-3 (M1))
Program Officer
Mckeon, Catherine T
Project Start
2001-09-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$150,082
Indirect Cost
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239