Long-Term Follow-up of Foamy Viral Vector-Mediated Gene Therapy for Canine Leukocyte Adhesion Deficiency

• Published in: Molecular therapy 2013-05, Vol.21 (5), p.964-972
• Main Authors: Bauer, Thomas R, Tuschong, Laura M, Calvo, Katherine R, Shive, Heather R, Burkholder, Tanya H, Karlsson, Eleanor K, West, Robert R, Russell, David W, Hickstein, Dennis D
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD34 - metabolism; Bacterial infections; Blood; Bone Marrow; CD18 Antigens - metabolism; Disease; Disease Models, Animal; Dogs; Female; Follow-Up Studies; Gene therapy; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors - genetics; Genotype & phenotype; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - metabolism; Humans; Leukemia; Leukocyte Count; Leukocyte-Adhesion Deficiency Syndrome - genetics; Leukocyte-Adhesion Deficiency Syndrome - therapy; Leukocytes; Leukocytes - metabolism; Lymphocytes; Male; Medical research; Neutrophils; Original; Spumavirus - genetics; Stem cells; T-Lymphocyte Subsets - metabolism; Transduction, Genetic; Transplants & implants; Vectors (Biology); Virus Integration
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2013.34

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.