T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates

被引:252
作者
Kohn, DB
Hershfield, MS
Carbonaro, D
Shigeoka, A
Brooks, J
Smogorzewska, EM
Barsky, LW
Chan, R
Burotto, F
Annett, G
Nolta, JA
Crooks, G
Kapoor, N
Elder, M
Wara, D
Bowen, T
Madsen, E
Snyder, FF
Bastian, J
Muul, L
Blaese, RM
Weinberg, K
Parkman, R
机构
[1] Childrens Hosp Los Angeles, Div Immunol Res Bone Marrow Transplantat, Los Angeles, CA 90027 USA
[2] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[3] Univ Utah, Dept Pediat, Salt Lake City, UT 84132 USA
[4] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[5] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5CT, Canada
[6] Childrens Hosp & Hlth Ctr, San Diego, CA 92123 USA
[7] Natl Ctr Human Genome Res, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1038/nm0798-775
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:775 / 780
页数:6
相关论文
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