SCID-Xl is catastrophic immunodeficiency disorder caused by mutations within the common gamma chain (yc) gene. While stem cell transplantation using a matched sibling donor can be curative, most patients lack optimal donors leading to poorer outcomes. Gene replacement has many theoretical advantages as an alternative therapeutic approach for SCID-Xl;and pioneering clinical studies using gammaretroviral yc delivery lead to both significant benefit as well as unanticipated adverse events due to viral enhancer triggered leukemogenesis. The overarching hypothesis of this PPG is that both the efficacy and safety of yc gene delivery can be significantly improved using recombinant foamy virus (FV) based vectors. Studies in Project 1 are designed to test the hypotheses that yc FV vectors devoid of viral enhancers (with or without additional enhancer blocking elements flanking the transcriptional cassette) will exhibit levels of transgene expression sufficient for functional rescue in vivo while concurrently showing reduced genotoxicity.
The aims of Project 1 are designed to test these hypotheses via detailed phenotypic, functional, and molecular analysis in both: 1) a small animal model of SCID-Xl and 2) hematopoietic stem cells (HSC) derived from SCID-Xl patients. Our specific studies will include efficacy and safety assessment of 1) EFIa-hu-yc FV vectors in vivo in myeloablated vs. non-myeloablated murine SCID-Xl recipients;and in alternative in vitro transactivation assays;2) Preclinical and GMP-grade 1^'generation yc FV in transduced SCID-Xl patient CD34* BM cells;and 3) Candidate insulated 2

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI097100-02
Application #
8567342
Study Section
Special Emphasis Panel (ZAI1-JTS-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$217,818
Indirect Cost
$35,930
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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