Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 20 October 1995:
Vol. 270. no. 5235, pp. 470 - 475
DOI: 10.1126/science.270.5235.470
Prev | Table of Contents | Next

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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency.
A. Aiuti, F. Cattaneo, S. Galimberti, U. Benninghoff, B. Cassani, L. Callegaro, S. Scaramuzza, G. Andolfi, M. Mirolo, I. Brigida, et al. (2009)
N. Engl. J. Med. 360, 447-458
   Abstract »    Full Text »    PDF »
Gene Therapy Fulfilling Its Promise.
D. B. Kohn and F. Candotti (2009)
N. Engl. J. Med. 360, 518-521
   Full Text »    PDF »
Stable transduction of quiescent T cells without induction of cycle progression by a novel lentiviral vector pseudotyped with measles virus glycoproteins.
C. Frecha, C. Costa, D. Negre, E. Gauthier, S. J. Russell, F.-L. Cosset, and E. Verhoeyen (2008)
Blood 112, 4843-4852
   Abstract »    Full Text »    PDF »
Interfering RNA-mediated purine analog resistance for in vitro and in vivo cell selection.
C. C. Porter and J. DeGregori (2008)
Blood 112, 4466-4474
   Abstract »    Full Text »    PDF »
Hematopoietic stem cell transplantation: 40 years of continuous progress and evolution.
F. Porta, F. Locatelli, and G. R. Burgio (2008)
Haematologica 93, 1607-1610
   Full Text »    PDF »
Development of gene therapy for blood disorders.
A. W. Nienhuis (2008)
Blood 111, 4431-4444
   Abstract »    Full Text »    PDF »
Update on clinical gene therapy in childhood.
W. Qasim, H Bobby Gaspar, and A. J Thrasher (2007)
Arch. Dis. Child. 92, 1028-1031
   Abstract »    Full Text »    PDF »
Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects.
A. Mortellaro, R. J. Hernandez, M. M. Guerrini, F. Carlucci, A. Tabucchi, M. Ponzoni, F. Sanvito, C. Doglioni, C. D. Serio, L. Biasco, et al. (2006)
Blood 108, 2979-2988
   Abstract »    Full Text »    PDF »
Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes.
B. Clemenceau, N. Congy-Jolivet, G. Gallot, R. Vivien, J. Gaschet, G. Thibault, and H. Vie (2006)
Blood 107, 4669-4677
   Abstract »    Full Text »    PDF »
Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy.
S. S. T.-D. Ravin, D. R. Kennedy, N. Naumann, J. S. Kennedy, U. Choi, B. J. Hartnett, G. F. Linton, N. L. Whiting-Theobald, P. F. Moore, W. Vernau, et al. (2006)
Blood 107, 3091-3097
   Abstract »    Full Text »    PDF »
Survival of the fittest: in vivo selection and stem cell gene therapy.
T. Neff, B. C. Beard, and H.-P. Kiem (2006)
Blood 107, 1751-1760
   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Type 1 Vectors with Alphavirus Envelope Glycoproteins Produced from Stable Packaging Cells.
B. L. Strang, Y. Takeuchi, T. Relander, J. Richter, R. Bailey, D. A. Sanders, M. K. L. Collins, and Y. Ikeda (2005)
J. Virol. 79, 1765-1771
   Abstract »    Full Text »    PDF »
The regulated long-term delivery of therapeutic proteins by using antigen-specific B lymphocytes.
K. Takacs, C. Du Roure, S. Nabarro, N. Dillon, J. H. McVey, Z. Webster, A. MacNeil, I. Bartok, C. Higgins, D. Gray, et al. (2004)
PNAS 101, 16298-16303
   Abstract »    Full Text »    PDF »
Capillary Electrophoresis in Diagnosis and Monitoring of Adenosine Deaminase Deficiency.
F. Carlucci, A. Tabucchi, A. Aiuti, F. Rosi, F. Floccari, R. Pagani, and E. Marinello (2003)
Clin. Chem. 49, 1830-1838
   Abstract »    Full Text »    PDF »
In Vitro Generation and Life Span Extension of Human Papillomavirus Type 16-Specific, Healthy Donor-Derived CTL Clones.
M. W. J. Schreurs, K. B. J. Scholten, E. W. M. Kueter, J. J. Ruizendaal, C. J. L. M. Meijer, and E. Hooijberg (2003)
J. Immunol. 171, 2912-2921
   Abstract »    Full Text »    PDF »
Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence.
S. Cavalieri, S. Cazzaniga, M. Geuna, Z. Magnani, C. Bordignon, L. Naldini, and C. Bonini (2003)
Blood 102, 497-505
   Abstract »    Full Text »    PDF »
Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial.
L. M. Muul, L. M. Tuschong, S. L. Soenen, G. J. Jagadeesh, W. J. Ramsey, Z. Long, C. S. Carter, E. K. Garabedian, M. Alleyne, M. Brown, et al. (2003)
Blood 101, 2563-2569
   Abstract »    Full Text »    PDF »
The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development.
R. Schotte, M.-C. Rissoan, N. Bendriss-Vermare, J.-M. Bridon, T. Duhen, K. Weijer, F. Briere, and H. Spits (2003)
Blood 101, 1015-1023
   Abstract »    Full Text »    PDF »
Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning.
A. Aiuti, S. Slavin, M. Aker, F. Ficara, S. Deola, A. Mortellaro, S. Morecki, G. Andolfi, A. Tabucchi, F. Carlucci, et al. (2002)
Science 296, 2410-2413
   Abstract »    Full Text »    PDF »
Efficient gene transfer into human primary blood lymphocytes by surface-engineered lentiviral vectors that display a T cell-activating polypeptide.
M. Maurice, E. Verhoeyen, P. Salmon, D. Trono, S. J. Russell, and F.-L. Cosset (2002)
Blood 99, 2342-2350
   Abstract »    Full Text »    PDF »
Adenosine deaminase deficiency with mosaicism for a "second-site suppressor" of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy.
F. X. Arredondo-Vega, I. Santisteban, E. Richard, P. Bali, M. Koleilat, M. Loubser, A. Al-Ghonaium, M. Al-Helali, and M. S. Hershfield (2002)
Blood 99, 1005-1013
   Abstract »    Full Text »    PDF »
T-cell lines from 2 patients with adenosine deaminase (ADA) deficiency showed the restoration of ADA activity resulted from the reversion of an inherited mutation.
T. Ariga, N. Oda, K. Yamaguchi, N. Kawamura, H. Kikuta, S. Taniuchi, Y. Kobayashi, K. Terada, H. Ikeda, M. S. Hershfield, et al. (2001)
Blood 97, 2896-2899
   Abstract »    Full Text »    PDF »
Current topic: Severe combined immunodeficiency{---}molecular pathogenesis and diagnosis.
H B Gaspar, K C Gilmour, and A M Jones (2001)
Arch. Dis. Child. 84, 169-173
   Full Text »
Nonmyeloablative Immunosuppressive Regimen Prolongs In Vivo Persistence of Gene-Modified Autologous T Cells in a Nonhuman Primate Model.
C. Berger, M.-L. Huang, M. Gough, P. D. Greenberg, S. R. Riddell, and H.-P. Kiem (2001)
J. Virol. 75, 799-808
   Abstract »    Full Text »
Hematologic Aspects of HIV/AIDS.
A. M. Levine, D. T. Scadden, J. A. Zaia, and A. Krishnan (2001)
Hematology 2001, 463-478
   Abstract »    Full Text »    PDF »
Lentiviral-mediated gene transfer into human lymphocytes: role of HIV-1 accessory proteins.
D. Chinnasamy, N. Chinnasamy, M. J. Enriquez, M. Otsu, R. A. Morgan, and F. Candotti (2000)
Blood 96, 1309-1316
   Abstract »    Full Text »    PDF »
Mild preconditioning and low-level engraftment confer methotrexate resistance in mice transplanted with marrow expressing drug-resistant dihydrofolate reductase activity.
R. I. James, C. A. Warlick, M. D. Diers, R. Gunther, and R. S. McIvor (2000)
Blood 96, 1334-1341
   Abstract »    Full Text »    PDF »
Highly efficient gene transfer in naive human T cells with a murine leukemia virus-based vector.
V. Dardalhon, S. Jaleco, C. Rebouissou, C. Ferrand, N. Skander, L. Swainson, P. Tiberghien, H. Spits, N. Noraz, and N. Taylor (2000)
Blood 96, 885-893
   Abstract »    Full Text »    PDF »
Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease.
M. Cavazzana-Calvo, S. Hacein-Bey, G. d. S. Basile, F. Gross, E. Yvon, P. Nusbaum, F. Selz, C. Hue, S. Certain, J. Casanova, et al. (2000)
Science 288, 669-672
   Abstract »    Full Text »
High levels of lymphoid expression of enhanced green fluorescent protein in nonhuman primates transplanted with cytokine-mobilized peripheral blood CD34+ cells.
R. E. Donahue, R. P. Wersto, J. A. Allay, B. A. Agricola, M. E. Metzger, A. W. Nienhuis, D. A. Persons, and B. P. Sorrentino (2000)
Blood 95, 445-452
   Abstract »    Full Text »    PDF »
Immunogenetics: changing the face of immunodeficiency.
A. M Jones and H. B Gaspar (2000)
J. Clin. Pathol. 53, 60-65
   Full Text »    PDF »
Bone Marrow Transplantation for Non-Malignant Disease.
K. M. Sullivan, R. Parkman, and M. C. Walters (2000)
Hematology 2000, 319-338
   Abstract »    Full Text »    PDF »
Reversal of Metabolic Block in Glycolysis by Enzyme Replacement in Triosephosphate Isomerase-Deficient Cells.
A. Ationu, A. Humphries, M. R.A. Lalloz, R. Arya, B. Wild, J. Warrilow, J. Morgan, A. J. Bellingham, and D. M. Layton (1999)
Blood 94, 3193-3198
   Abstract »    Full Text »    PDF »
Prospects for in Utero Human Gene Therapy.
E. D. Zanjani and W. F. Anderson (1999)
Science 285, 2084-2088
   Abstract »    Full Text »
In Vivo Kinetics of Transduced Cells in Peripheral T Cell-Directed Gene Therapy: Role of CD8+ Cells in Improved Immunological Function in an Adenosine Deaminase (ADA)-SCID Patient.
N. Kawamura, T. Ariga, M. Ohtsu, I. Kobayashi, M. Yamada, A. Tame, H. Furuta, M. Okano, M. Egashira, N. Niikawa, et al. (1999)
J. Immunol. 163, 2256-2261
   Abstract »    Full Text »    PDF »
Correction of Uroporphyrinogen Decarboxylase Deficiency (Hepatoerythropoietic Porphyria) in Epstein-Barr Virus-Transformed B-Cell Lines by Retrovirus-Mediated Gene Transfer: Fluorescence-Based Selection of Transduced Cells.
A. Fontanellas, F. Mazurier, F. Moreau-Gaudry, F. Belloc, C. Ged, and H. de Verneuil (1999)
Blood 94, 465-474
   Abstract »    Full Text »    PDF »
Natural Killer Cell-mediated Lysis of Autologous Cells Modified by Gene Therapy.
C. Liberatore, M. Capanni, N. Albi, I. Volpi, E. Urbani, L. Ruggeri, A. Mencarelli, F. Grignani, and A. Velardi (1999)
J. Exp. Med. 189, 1855-1862
   Abstract »    Full Text »    PDF »
Transcriptional Targeting of Retroviral Vectors to the Erythroblastic Progeny of Transduced Hematopoietic Stem Cells.
A. Grande, B. Piovani, A. Aiuti, S. Ottolenghi, F. Mavilio, and G. Ferrari (1999)
Blood 93, 3276-3285
   Abstract »    Full Text »    PDF »
One-Day Ex Vivo Culture Allows Effective Gene Transfer Into Human Nonobese Diabetic/Severe Combined Immune-Deficient Repopulating Cells Using High-Titer Vesicular Stomatitis Virus G Protein Pseudotyped Retrovirus.
V. I. Rebel, M. Tanaka, J.-S. Lee, S. Hartnett, M. Pulsipher, D. G. Nathan, R. C. Mulligan, and C. A. Sieff (1999)
Blood 93, 2217-2224
   Abstract »    Full Text »    PDF »
Stable transduction of quiescent CD34+CD38- human hematopoietic cells by HIV-1-based lentiviral vectors.
S. S. Case, M. A. Price, C. T. Jordan, X. J. Yu, L. Wang, G. Bauer, D. L. Haas, D. Xu, R. Stripecke, L. Naldini, et al. (1999)
PNAS 96, 2988-2993
   Abstract »    Full Text »    PDF »
Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency.
K. D. Bunting, K. J. Flynn, J. M. Riberdy, P. C. Doherty, and B. P. Sorrentino (1999)
PNAS 96, 232-237
   Abstract »    Full Text »    PDF »
Enhanced Retroviral Transduction of 5-Fluorouracil-Resistant Human Bone Marrow (Stem) Cells Using a Genetically Modified Packaging Cell Line.
J. Povey, N. Weeratunge, C. Marden, A. Sehgal, A. Thrasher, and C. Casimir (1998)
Blood 92, 4080-4089
   Abstract »    Full Text »    PDF »
High Efficiency Gene Transfer to Human Hematopoietic SCID-Repopulating Cells Under Serum-Free Conditions.
A. J. Schilz, G. Brouns, O. G. Ottmann, D. Hoelzer, A. A. Fauser, A. J. Thrasher, and M. Grez (1998)
Blood 92, 3163-3171
   Abstract »    Full Text »    PDF »
Efficient Class II Major Histocompatibility Complex Presentation of Endogenously Synthesized Hepatitis C Virus Core Protein by Epstein-Barr Virus-Transformed B-Lymphoblastoid Cell Lines to CD4+ T Cells.
M. Chen, M. Shirai, Z. Liu, T. Arichi, H. Takahashi, and M. Nishioka (1998)
J. Virol. 72, 8301-8308
   Abstract »    Full Text »    PDF »
Sustained Gene Expression in Retrovirally Transduced, Engrafting Human Hematopoietic Stem Cells and Their Lympho-Myeloid Progeny.
L. Cheng, C. Du, C. Lavau, S. Chen, J. Tong, B. P. Chen, R. Scollay, R. G. Hawley, and B. Hill (1998)
Blood 92, 83-92
   Abstract »    Full Text »    PDF »
High-Efficiency Gene Transfer into Normal and Adenosine Deaminase-Deficient T Lymphocytes Is Mediated by Transduction on Recombinant Fibronectin Fragments.
K. E. Pollok, H. Hanenberg, T. W. Noblitt, W. L. Schroeder, I. Kato, D. Emanuel, and D. A. Williams (1998)
J. Virol. 72, 4882-4892
   Abstract »    Full Text »    PDF »
Scaffold Attachment Region-Mediated Enhancement of Retroviral Vector Expression in Primary T Cells.
M. Agarwal, T. W. Austin, F. Morel, J. Chen, E. Bohnlein, and I. Plavec (1998)
J. Virol. 72, 3720-3728
   Abstract »    Full Text »    PDF »
Adenosine Deaminase-deficient Mice Generated Using a Two-stage Genetic Engineering Strategy Exhibit a Combined Immunodeficiency.
M. R. Blackburn, S. K. Datta, and R. E. Kellems (1998)
J. Biol. Chem. 273, 5093-5100
   Abstract »    Full Text »    PDF »
Primary Immunodeficiency Diseases in Adults.
S. H. Sicherer and J. A. Winkelstein (1998)
JAMA 279, 58-61
   Full Text »    PDF »
Successful Peripheral T-Lymphocyte-Directed Gene Transfer for a Patient With Severe Combined Immune Deficiency Caused by Adenosine Deaminase Deficiency.
M. Onodera, T. Ariga, N. Kawamura, I. Kobayashi, M. Ohtsu, M. Yamada, A. Tame, H. Furuta, M. Okano, S. Matsumoto, et al. (1998)
Blood 91, 30-36
   Abstract »    Full Text »    PDF »
Gene therapy.
M. A. Kay, D. Liu, and P. M. Hoogerbrugge (1997)
PNAS 94, 12744-12746
   Abstract »    Full Text »    PDF »
Development of a Novel Selective Amplifier Gene for Controllable Expansion of Transduced Hematopoietic Cells.
K. Ito, Y. Ueda, M. Kokubun, M. Urabe, T. Inaba, H. Mano, H. Hamada, T. Kitamura, H. Mizoguchi, T. Sakata, et al. (1997)
Blood 90, 3884-3892
   Abstract »    Full Text »    PDF »
Successful Reconstitution of Human Hematopoiesis in the SCID-hu Mouse by Genetically Modified, Highly Enriched Progenitors Isolated From Fetal Liver.
L. Humeau, C. Chabannon, M. T. Firpo, P. Mannoni, C. Bagnis, M.-G. Roncarolo, and R. Namikawa (1997)
Blood 90, 3496-3506
   Abstract »    Full Text »    PDF »
Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.
H. L. Malech, P. B. Maples, N. Whiting-Theobald, G. F. Linton, S. Sekhsaria, S. J. Vowells, F. Li, J. A. Miller, E. DeCarlo, S. M. Holland, et al. (1997)
PNAS 94, 12133-12138
   Abstract »    Full Text »    PDF »
Differential Maintenance of Primitive Human SCID-Repopulating Cells, Clonogenic Progenitors, and Long-Term Culture-Initiating Cells After Incubation on Human Bone Marrow Stromal Cells.
O. I. Gan, B. Murdoch, A. Larochelle, and J. E. Dick (1997)
Blood 90, 641-650
   Abstract »    Full Text »    PDF »
Stem Cell-Based Gene Therapy.
C. Bagnis and P. Mannoni (1997)
Oncologist 2, 196-202
   Full Text »    PDF »
Retroviral Gene Transduction of Adult Peripheral Blood or Marrow-Derived CD34+ Cells for Six Hours Without Growth Factors or on Autologous Stroma Does Not Improve Marking Efficiency Assessed In Vivo.
R.V.B. Emmons, S. Doren, J. Zujewski, M. Cottler-Fox, C.S. Carter, K. Hines, J.A. O'Shaughnessy, S.F. Leitman, J.J. Greenblatt, K. Cowan, et al. (1997)
Blood 89, 4040-4046
   Abstract »    Full Text »    PDF »
Inhibition of Human Immunodeficiency Virus-1 (HIV-1) Replication After Transduction of Granulocyte Colony-Stimulating Factor-Mobilized CD34+ Cells From HIV-1-Infected Donors Using Retroviral Vectors Containing Anti-HIV-1 Genes.
G. Bauer, P. Valdez, K. Kearns, I. Bahner, S. F. Wen, J. A. Zaia, and D. B. Kohn (1997)
Blood 89, 2259-2267
   Abstract »    Full Text »    PDF »
Efficient In Vivo Marking of Primary CD4+ T Lymphocytes in Nonhuman Primates Using a Gibbon Ape Leukemia Virus-Derived Retroviral Vector.
B. A. Bunnell, M. Metzger, E. Byrne, R. A. Morgan, and R. E. Donahue (1997)
Blood 89, 1987-1995
   Abstract »    Full Text »    PDF »
Modest Success for Gene Therapy in Immunodeficiency.
(1995)
Journal Watch Dermatology 1995, 14
   Full Text »
MODEST SUCCESS FOR GENE THERAPY IN IMMUNODEFICIENCY.
(1995)
Journal Watch (General) 1995, 4
   Full Text »
The Use of Enzyme Therapy to Regulate the Metabolic and Phenotypic Consequences of Adenosine Deaminase Deficiency in Mice. DIFFERENTIAL IMPACT ON PULMONARY AND IMMUNOLOGIC ABNORMALITIES.
M. R. Blackburn, M. Aldrich, J. B. Volmer, W. Chen, H. Zhong, S. Kelly, M. S. Hershfield, S. K. Datta, and R. E. Kellems (2000)
J. Biol. Chem. 275, 32114-32121
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)