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Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning
Abstract
Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)–deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated. Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions (including antigen-specific responses), and lower toxic metabolites. Both patients are currently at home and clinically well, with normal growth and development. These results indicate the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID.
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“The earliest successful human gene therapy trials by Aiuti et al. 13 and Cavazzana-Calvo et al. 14 utilized γ-RVV and many of the techniques developed in the 1980s.”
From Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy (2025) · cites this paper as [13]
In the citing paper
“The major advance came from trials at San Raffaele Hospital and the Telethon Institute for Gene Therapy in Milan, Italy, that administered relatively low dosages of the chemotherapy drug busulfan, eliminating HSC in the marrow before reinfusion of the γ-retroviral vector transduced HSC to facilitate engraftment.13”
From Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy (2025) · cites this paper as [13]
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- We thank the nurses in the BMT and Gene Therapy Program Department of Hematology at the Scientific Institute H. S. Raffaele and at Hadassah University for skilled and dedicated care. We thank S. Yoshimura for providing CH-296 fibronectin fragment (Takara); Y. Gelfand for excellent technical assistance in handling cells of Pt1; C. Mocchetti N. Carballido and J. Carballido for help with SCID-hu mice; M. S. Hershfield for initial help in setting up the biochemical assays; R. Sciarretta Birolo for PCR analysis; and L. Parma and G. Torriani for flow cytometry and cell sorting. HSR-TIGET is supported by the Italian Telethon Foundation. Supporting Online Material www.sciencemag.org/cgi/content/full/296/5577/2410/DC1 Materials and Methods
Cited by
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Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., Clappier, E., Caccavelli, L., Delabesse, E., Beldjord, K., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35700 · Cited by 1,854
Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018) · Science · doi:10.1126/science.aan4672 · Cited by 1,410
Lombardo, A., Genovese, P., Beausejour, C. M., Colleoni, S., Lee, Y.-L., Kim, K. A., Ando, D., Urnov, F. D., Galli, C., Gregory, P. D., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1353 · Cited by 845
Holt, N., Wang, J., Kim, K., Friedman, G., Wang, X., Taupin, V., Crooks, G. M., Kohn, D. B., Gregory, P. D., Holmes, M. C., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1663 · Cited by 677
Gene therapy for Wiskott-Aldrich syndrome–long-term efficacy and genotoxicity
Braun, C. J., Boztug, K., Paruzynski, A., Witzel, M., Schwarzer, A., Rothe, M., Modlich, U., Beier, R., Göhring, G., Steinemann, D., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007280 · Cited by 562
Metadata
- Authors
- Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., Marinello, E., Cattaneo, F., Vai, S., Servida, P., Miniero, R., Roncarolo, M. G., & Bordignon, C.
- Affiliations
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
- Departments of Bone Marrow Transplantation and Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
- Institute of Biochemistry and Enzymology, University of Siena, Siena, Italy.
- BMT and Gene Therapy Program, Scientific Institute H. S. Raffaele;
- Department of Biological and Clinical Science, University of Turin, Turin, Italy.
- Venue
- Science
- Published
- 2002-06-28
- Volume
- 296
- Issue
- 5577
- Pages
- 2410-2413
- ISSN
- 0036-8075
- 1095-9203
- Cited by
- 975
- References
- 0
- Language
- en
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- Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., Marinello, E., Cattaneo, F., Vai, S., Servida, P., Miniero, R., Roncarolo, M. G., & Bordignon, C. (2002). Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning. Science. https://doi.org/10.1126/science.1070104
