title: Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy.
abstract: X-linked severe combined immunodeficiency (XSCID) is characterized by profound immunodeficiency and early mortality, the only potential cure being hematopoietic stem cell (HSC) transplantation or gene therapy. Current clinical gene therapy protocols targeting HSCs are based upon ex vivo gene transfer, potentially limited by the adequacy of HSC harvest, transduction efficiencies of repopulating HSCs, and the potential loss of their engraftment potential during ex vivo culture. We demonstrate an important proof of principle by showing achievement of durable immune reconstitution in XSCID dogs following intravenous injection of concentrated RD114-pseudotyped retrovirus vector encoding the corrective gene, the interleukin-2 receptor gamma chain (gamma c). In 3 of 4 dogs treated, normalization of numbers and function of T cells were observed. Two long-term-surviving animals (16 and 18 months) showed significant marking of B lymphocytes and myeloid cells, normalization of IgG levels, and protective humoral immune response to immunization. There were no adverse effects from in vivo gene therapy, and in one dog that reached sexual maturity, sparing of gonadal tissue from gene transfer was demonstrated. This is the first demonstration that in vivo gene therapy targeting HSCs can restore both cellular and humoral immunity in a large-animal model of a fatal immunodeficiency.
authors.affiliation: Laboratory of Host Defenses, NIAID, NIH, Building 10-CRC, Room 5-3750, 10 Center Drive, Bethesda, MD 20892-1456, USA. sderavin@niaid.nih.gov
authors.forename: Suk See
authors.initials: SS
authors.lastname: Ting-De Ravin
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Kennedy
authors.forename: Nora
authors.initials: N
authors.lastname: Naumann
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kennedy
authors.forename: Uimook
authors.initials: U
authors.lastname: Choi
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hartnett
authors.forename: Gilda F
authors.initials: GF
authors.lastname: Linton
authors.forename: Narda L
authors.initials: NL
authors.lastname: Whiting-Theobald
authors.forename: Peter F
authors.initials: PF
authors.lastname: Moore
authors.forename: William
authors.initials: W
authors.lastname: Vernau
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felsburg
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007114:Immunization; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000276:immunology; D020127:Recovery of Function / Q000235:genetics* / Q000276:immunology; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods; D014182:Transplantation, Autologous
chemical_list: D015375:Receptors, Interleukin-2