T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates.
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.
Kohn
D B
DB
Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital, Los Angeles, California 90027, USA.
Hershfield
M S
MS
Carbonaro
D
D
Shigeoka
A
A
Brooks
J
J
Smogorzewska
E M
EM
Barsky
L W
LW
Chan
R
R
Burotto
F
F
Annett
G
G
Nolta
J A
JA
Crooks
G
G
Kapoor
N
N
Elder
M
M
Wara
D
D
Bowen
T
T
Madsen
E
E
Snyder
F F
FF
Bastian
J
J
Muul
L
L
Blaese
R M
RM
Weinberg
K
K
Parkman
R
R
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
D018952:Antigens, CD34; D011092:Polyethylene Glycols; D000243:Adenosine Deaminase