title: Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors.
abstract: Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.
authors.affiliation: Experimental Transplantation and Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC1203, Building 10-CRC, Room 3-3330, Bethesda, Maryland 20892, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: James M
authors.initials: JM
authors.lastname: Allen
authors.forename: Mehreen
authors.initials: M
authors.lastname: Hai
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Iram F
authors.initials: IF
authors.lastname: Khan
authors.forename: Erik M
authors.initials: EM
authors.lastname: Olson
authors.forename: Rima L
authors.initials: RL
authors.lastname: Adler
authors.forename: Tanya H
authors.initials: TH
authors.lastname: Burkholder
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Gu
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 / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000628:therapy* / Q000662:veterinary; D007962:Leukocytes / Q000166:cytology*; D008214:Lymphocytes / Q000378:metabolism; D010641:Phenotype; D016092:Spumavirus / Q000235:genetics*
chemical_list: D018952:Antigens, CD34