Foamy virus vector-mediated gene correction of a mouse model of Wiskott-Aldrich syndrome.
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and immunodeficiency. Hematopoietic cell transplantation can cure the disease and gene therapy is being tested as an alternative treatment option. In this study, we assessed the use of foamy virus (FV) vectors as a gene transfer system for WAS, using a Was knockout (KO) mouse model. Preliminary experiments using FV vectors expressing the green fluorescent protein under the transcriptional control of the endogenous WAS promoter or a ubiquitously acting chromatin opening element allowed us to define transduction conditions resulting in high (>40%) and long-term in-vivo marking of blood cells after transplantation. In following experiments, Was KO mice were treated with FV vectors containing the human WAS complementary DNA (cDNA). Transplanted animals expressed the WAS protein (WASp) in T and B lymphocytes, as well as platelets and showed restoration of both T-cell receptor-mediated responses and B-cell migration. We also observed recovery of platelet adhesion and podosome formation in dendritic cells (DCs) of treated mice. These data demonstrate that FV vectors can be effective for hematopoietic stem cell (HSC)-directed gene correction of WAS.
Disorders of Immunity Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4442, USA.
Toru
T
Uchiyama
Marsilio
M
Adriani
G Jayashree
GJ
Jagadeesh
Adam
A
Paine
Fabio
F
Candotti
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016092:Spumavirus / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D016662:Virus Integration; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism
D051316:Wiskott-Aldrich Syndrome Protein