Nature Medicine
4, 775 - 780 (1998)
doi:10.1038/nm0798-775
T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonatesDonald B. Kohn1, 10, Michal S. Hershfield2, Denise Carbonaro1, Ann Shigeoka3, Judith Brooks1, E. Monika Smogorzewska1, Lora W. Barsky1, Raymond Chan1, Felix Burotto1, Geralyn Annett1, Jan A. Nolta1, Gay Crooks1, Neena Kapoor1, Melissa Eldetr4, Diane Wara4, Thomas Bowen5, Edward Madsen6, Floyd F. Synder7, John Bastian8, Linda Muul9, R. Michael Blaese9, Kenneth Weinberg1
& Robertson Parkman1
1Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital, Los Angeles, 4650 Sunset Blvd, Los Angeles, California 90027, USA
2Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
3Department of Pediatrics, University of Utah Health Sciences, Salt Lake City, Utah 84132, USA
4Department of Pediatrics, University of California at San Francisco, San Francisco, California 94143, USA
5#705 South Tower, 3031 Hospital Drive NW, Calgary, Alberta, Canada T2N 2T8
6590 North Hospital Drive, Price, Utah 84501, USA
7Alberta Children's Hospital, Calgary, Canada T2T 5CT
8Children's Hospital and Health Center, San Diego, California 92123, USA
9Clinical Gene Therapy Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892, USA Correspondence should be addressed to D.B.K.
10Correspondence should be addressed to D.B.K. Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for genecorrected 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.
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