title: Long-term follow-up of foamy viral vector-mediated gene therapy for canine leukocyte adhesion deficiency.
abstract: The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunodeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4-7 years) of four dogs with canine leukocyte adhesion deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34(+) hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18(+) leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with leukocyte adhesion deficiency type 1 (LAD-1) in a human gene therapy clinical trial.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.forename: Heather R
authors.initials: HR
authors.lastname: Shive
authors.forename: Tanya H
authors.initials: TH
authors.lastname: Burkholder
authors.forename: Eleanor K
authors.initials: EK
authors.lastname: Karlsson
authors.forename: Robert R
authors.initials: RR
authors.lastname: West
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow; D018821:CD18 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics* / Q000628:therapy*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D016092:Spumavirus / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D014161:Transduction, Genetic; D016662:Virus Integration
chemical_list: D018952:Antigens, CD34; D018821:CD18 Antigens