title: Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma.
abstract: We have previously shown that in vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo γ-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 10(6) transduced CD34(+) cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA(+) (naïve) T cells. However, this was followed by a steady decrease in CD45RA(+) T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to γ-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Kennedy
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hartnett
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kennedy
authors.forename: William
authors.initials: W
authors.lastname: Vernau
authors.forename: Peter F
authors.initials: PF
authors.lastname: Moore
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Malley
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Paula S
authors.initials: PS
authors.lastname: Henthorn
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felsburg
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D004283:Dog Diseases / Q000276:immunology* / Q000628:therapy; D004285:Dogs; D005434:Flow Cytometry / Q000662:veterinary; D015316:Genetic Therapy / Q000662:veterinary*; D005822:Genetic Vectors / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy / Q000662:veterinary*; D016133:Polymerase Chain Reaction / Q000662:veterinary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology / Q000628:therapy / Q000662:veterinary*
chemical_list: D018952:Antigens, CD34; D011948:Receptors, Antigen, T-Cell