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Science 20 October 1995:
Vol. 270. no. 5235, pp. 470 - 475
DOI: 10.1126/science.270.5235.470
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Reports

Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA Immunodeficient Patients

Claudio Bordignon (1),  Luigi D. Notarangelo,  Nadia Nobili,  Giuliana Ferrari,  Giulia Casorati,  Paola Panina,  Evelina Mazzolari,  Daniela Maggioni,  Claudia Rossi,  Paolo Servida,  Alberto G. Ugazio,  Fulvio Mavilio

Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two different retroviral vectors were used to transfer ex vivo the human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients undergoing exogenous enzyme replacement therapy. After 2 years of treatment, long-term survival of T and B lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was demonstrated and resulted in normalization of the immune repertoire and restoration of cellular and humoral immunity. After discontinuation of treatment, T lymphocytes, derived from transduced peripheral blood lymphocytes, were progressively replaced by marrow-derived T cells in both patients. These results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny.


C. Bordignon, N. Nobili, G. Ferrari, D. Maggioni, C. Rossi, P. Servida, F. Mavilio, Telethon Gene Therapy Program for Genetic Diseases, DIBIT, Istituto Scientifico H. S. Raffaele, Milan, Italy.
L. D. Notarangelo, E. Mazzolari, A. G. Ugazio, Department of Pediatrics, University of Brescia Medical School, Brescia, Italy.
G. Casorati, Unità di Immunochimica, DIBIT, Istituto Scientifico H. S. Raffaele, Milan, Italy.
P. Panina, Roche Milano Ricerche, Milan, Italy.
(1) To whom correspondence should be addressed.


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. Bagnis and P. Mannoni (1997)
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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G. Bauer, P. Valdez, K. Kearns, I. Bahner, S. F. Wen, J. A. Zaia, and D. B. Kohn (1997)
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   Abstract »    Full Text »    PDF »
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