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, 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
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