title: Intravenous injection of a foamy virus vector to correct canine SCID-X1.
abstract: Current approaches to hematopoietic stem cell (HSC) gene therapy involve the collection and ex vivo manipulation of HSCs, a process associated with loss of stem cell multipotency and engraftment potential. An alternative approach for correcting blood-related diseases is the direct intravenous administration of viral vectors, so-called in vivo gene therapy. In this study, we evaluated the safety and efficacy of in vivo gene therapy using a foamy virus vector for the correction of canine X-linked severe combined immunodeficiency (SCID-X1). In newborn SCID-X1 dogs, injection of a foamy virus vector expressing the human IL2RG gene resulted in an expansion of lymphocytes expressing the common γ chain and the development of CD3(+) T lymphocytes. CD3(+) cells expressed CD4 and CD8 coreceptors, underwent antigen receptor gene rearrangement, and demonstrated functional maturity in response to T-cell mitogens. Retroviral integration site analysis in 4 animals revealed a polyclonal pattern of integration in all dogs with evidence for dominant clones. These results demonstrate that a foamy virus vector can be administered with therapeutic benefit in the SCID-X1 dog, a clinically relevant preclinical model for in vivo gene therapy.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Burtner
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Brian C
authors.identifier: http://orcid.org/0000-0001-6480-0857
authors.initials: BC
authors.lastname: Beard
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Kennedy
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Martin E
authors.initials: ME
authors.lastname: Wohlfahrt
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Adair
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, WA;
authors.forename: Grant D
authors.initials: GD
authors.lastname: Trobridge
authors.affiliation: Department of Pediatrics and Immunology, University of Washington, Seattle, WA; and Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scharenberg
authors.affiliation: Department of Pediatrics and Immunology, University of Washington, Seattle, WA; and Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.affiliation: Department of Pediatrics and Immunology, University of Washington, Seattle, WA; and Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felsburg
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D057809:HEK293 Cells; D006801:Humans; D007275:Injections, Intravenous; D016092:Spumavirus; D016662:Virus Integration / Q000235:genetics; D053632:X-Linked Combined Immunodeficiency Diseases / Q000628:therapy*