title: T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates.
abstract: Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for gene-corrected T lymphocytes, which may overcome inefficient gene transfer. Four years after three newborns with this disease were given infusions of transduced autologous umbilical cord blood CD34+ cells, the frequency of gene-containing T lymphocytes has risen to 1-10%, whereas the frequencies of other hematopoietic and lymphoid cells containing the gene remain at 0.01-0.1%. Cessation of polyethylene glycol-conjugated adenosine deaminase enzyme replacement in one subject led to a decline in immune function, despite the persistence of gene-containing T lymphocytes. Thus, despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect.
authors.affiliation: Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital, Los Angeles, California 90027, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Kohn
authors.forename: M S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: D
authors.initials: D
authors.lastname: Carbonaro
authors.forename: A
authors.initials: A
authors.lastname: Shigeoka
authors.forename: J
authors.initials: J
authors.lastname: Brooks
authors.forename: E M
authors.initials: EM
authors.lastname: Smogorzewska
authors.forename: L W
authors.initials: LW
authors.lastname: Barsky
authors.forename: R
authors.initials: R
authors.lastname: Chan
authors.forename: F
authors.initials: F
authors.lastname: Burotto
authors.forename: G
authors.initials: G
authors.lastname: Annett
authors.forename: J A
authors.initials: JA
authors.lastname: Nolta
authors.forename: G
authors.initials: G
authors.lastname: Crooks
authors.forename: N
authors.initials: N
authors.lastname: Kapoor
authors.forename: M
authors.initials: M
authors.lastname: Elder
authors.forename: D
authors.initials: D
authors.lastname: Wara
authors.forename: T
authors.initials: T
authors.lastname: Bowen
authors.forename: E
authors.initials: E
authors.lastname: Madsen
authors.forename: F F
authors.initials: FF
authors.lastname: Snyder
authors.forename: J
authors.initials: J
authors.lastname: Bastian
authors.forename: L
authors.initials: L
authors.lastname: Muul
authors.forename: R M
authors.initials: RM
authors.lastname: Blaese
authors.forename: K
authors.initials: K
authors.lastname: Weinberg
authors.forename: R
authors.initials: R
authors.lastname: Parkman
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000276:immunology*; D002460:Cell Line; D005434:Flow Cytometry; D005787:Gene Frequency; D006098:Granulocytes / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D016513:Mice, SCID; D011092:Polyethylene Glycols; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014170:Transformation, Genetic; D014181:Transplantation Immunology / Q000276:immunology*; D014182:Transplantation, Autologous; D014470:Umbilical Cord
chemical_list: D018952:Antigens, CD34; D011092:Polyethylene Glycols; D000243:Adenosine Deaminase