SCID-Xl is catastrophic immunodeficiency disorder caused by mutations within the common gamma chain (?c) 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 ?c 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 ?c 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-?c 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 1st generation ?c FV in transduced SCID-Xl patient CD34* BM cells; and 3) Candidate insulated 2nd generation ?c FV vectors in HSC from SCID-Xl mice and human patients. Project 1 will utilize all 4 Cores and will interface on multiple levels with work within both Projects 2 and 3. In conjunction with data derived from Projects 2 and 3, our studies will provide key data regarding efficacy, safety and optimal vector design for future 1st and 2nd generation SCID-Xl FV vector clinical trials.

Public Health Relevance

SCID-Xl is severe immune disorder caused by mutations in the ?c gene. Gene therapy is predicted to provide a beneficial treatment for SCID-Xl. However, previous approaches, while beneficial, also lead to a high frequency of adverse events. The goal of this PPG is develop safe and effective SCID-Xl gene delivery using recombinant foamy virus (FV) based vectors. Studies in Project 1 are designed to test the idea that candidate clinical SCID-Xl FV vectors will rescue function in mouse and human models of SCID-Xl while concurrently showing reduced genotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
4P01AI097100-05
Application #
9117265
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101
Humbert, Olivier; Chan, Frieda; Rajawat, Yogendra S et al. (2018) Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy. Blood Adv 2:987-999
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Singh, Swati; Khan, Iram; Khim, Socheath et al. (2017) Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector. Mol Ther Methods Clin Dev 4:1-16
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Browning, Diana L; Trobridge, Grant D (2016) Insulators to Improve the Safety of Retroviral Vectors for HIV Gene Therapy. Biomedicines 4:
Browning, Diana L; Collins, Casey P; Hocum, Jonah D et al. (2016) Insulated Foamy Viral Vectors. Hum Gene Ther 27:255-66
Bii, Victor M; Trobridge, Grant D (2016) Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors. Cancers (Basel) 8:
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Nalla, Arun K; Williams, Theodore F; Collins, Casey P et al. (2016) Lentiviral vector-mediated insertional mutagenesis screen identifies genes that influence androgen independent prostate cancer progression and predict clinical outcome. Mol Carcinog 55:1761-1771
Humbert, Olivier; Gisch, Don W; Wohlfahrt, Martin E et al. (2016) Development of Third-generation Cocal Envelope Producer Cell Lines for Robust Lentiviral Gene Transfer into Hematopoietic Stem Cells and T-cells. Mol Ther 24:1237-46

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