Correspondence
LMO2 and Gene Therapy for Severe Combined Immunodeficiency
N Engl J Med 2004; 350:2526-2527June 10, 2004
- Article
To the Editor:
McCormack and Rabbitts (Feb. 26 issue)1 discuss the role of activation of the T-cell oncogene LMO2 in inducing clonal T-cell proliferation in two patients after gene therapy for X-linked severe combined immunodeficiency (SCID), a condition caused by mutation of the γc cytokine-receptor subunit gene. The authors point to a role of γc as a cofactor of clonal proliferation. However, there are no data to suggest that, as proposed, the expression of a CD25–γc interleukin-2–receptor complex by T-cell precursors will make these cells hypersensitive to interleukin-2, since signal transduction without the βR subunit of interleukin-2 is highly questionable.2 It is more likely that LMO2 and γc exert a synergistic effect in mediating T-cell growth. The mechanisms by which LMO2 triggers cell proliferation are also not necessarily homogeneous. Aberrant LMO2 expression in mice blocks T-cell differentiation at an immature, double-negative stage,1 whereas transgenic LMO2+ clones exhibit a mature phenotype,3 suggestive of a post-thymic role.
The authors mention the unpublished finding of another integration site in the LMO2 locus in a third patient. This finding should not be overemphasized, since this integration site was detected once and not in two more samples. In addition, it did not result in detectable LMO2 expression.
Age at the time of treatment is another cofactor associated with these serious adverse events.3 The likelihood that serious adverse events occurred by chance in the 2 youngest of the 13 successfully treated patients3 (and Gaspar et al.: unpublished data) is 1.2 percent ([2÷13]×[1÷12]). The characteristics of hematopoiesis in newborns4 could lead to a higher risk of insertion of the retrovirus in the LMO2 locus. Although this hypothesis requires testing, it may have an effect on the continuation of clinically successful trials of gene therapy for X-linked SCID. To select for gene therapy those patients with X-linked SCID who are older than a specified age limit is likely to be a strategy that combines efficacy and increased safety.
4 ReferencesAlain Fischer, M.D., Ph.D.
Salima Hacein-Bey Abina, Pharm.D., Ph.D.
INSERM Unité 429, 75015 Paris, France
fischer@necker.fr Adrian Thrasher, M.D., Ph.D.
Institute of Child Health, London WC1N 1EH, United KingdomChristof von Kalle, M.D., Ph.D.
Children's Hospital Research Foundation, Cincinnati, OH 45229Marina Cavazzana-Calvo, M.D., Ph.D.
INSERM Unité 429, 75015 Paris, France1
McCormack MP ,Rabbitts TH . Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2004;350:913-922
Full Text | Web of Science | Medline2
Sugamura K ,Asao H ,Kondo M , et al. The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 1996;14:179-205
CrossRef | Web of Science | Medline3
Hacein-Bey-Abina S ,Von Kalle C ,Schmidt M , et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302:415-419[Erratum, Science 2003;302:568.]
CrossRef | Web of Science | Medline4
Hirose J ,Kouro T ,Igarashi H ,Yokota T ,Sakaguchi N ,Kincade PW . A developing picture of lymphopoiesis in bone marrow. Immunol Rev 2002;189:28-40
CrossRef | Web of Science | Medline
To the Editor:
With regard to the excellent review article on gene therapy for X-linked SCID, I would like to clarify a point about lymphocyte phenotypes in SCID. The authors state, both in the text and in Figure 1B, that affected patients are deficient in T cells, B cells, and natural killer cells. Actually, patients with X-linked SCID are T-cell–negative and natural-killer-cell–negative but B-cell–positive (T–NK–B+).1
The common γ subunit, which is genetically defective in these patients, is essential for the normal function of the receptors for interleukins-2, 4, 7, 9, 15, and 21 on T cells and natural killer cells. The interleukin-7 receptor is crucial for the normal development of T cells, whereas the interleukin-15 receptor is necessary for the normal development of natural killer cells. Patients with X-linked SCID generally have normal numbers of B cells that function poorly because of the lack of T-cell help.
Adenosine deaminase deficiency is the cause of SCID that would result in the T–B–NK– phenotype. Patients with adenosine deaminase deficiency are not candidates for this type of gene therapy.
1 ReferencesBryan D. Stone, M.D.
Dartmouth–Hitchcock Medical Center, Keene, NH 034311
Buckley RH . Primary immunodeficiency disease due to defects in lymphocytes. N Engl J Med 2000;343:1313-1324
Full Text | Web of Science | Medline
Author/Editor Response
Stone points out that patients with X-linked SCID in fact have the T–NK–B+ phenotype but that adenosine deaminase–deficient patients with SCID lack B cells as well. Although it is true that B cells are usually present in patients with X-linked SCID, these cells are intrinsically defective1 (even in the presence of normal T cells), so that adequate function can usually be obtained only by engraftment with normal B cells. The portrayal of B-cell engraftment in Figure 1 of our article indicates the introduction of functional B cells into the patients. We also point out that adenosine deaminase deficiency is treatable by a regimen similar to that used in the X-linked SCID trial but by means of adenosine deaminase replacement.
Fischer and colleagues raise three issues that require further comment. Regarding the possible hypersensitivity of developing T cells to mitogenic signaling after overexpression of the common γc subunit of the interleukin-2 receptor (IL2Rγc), we note that human pro–T cells do respond to interleukin-2 in vitro, implying the presence of functional receptors. Moreover, the receptors for other IL2Rγc-containing receptors, including interleukin-7, are present in these cells,2 suggesting hypersensitivity to growth-factor signaling as a mechanism of synergy between IL2Rγc and LMO2 in oncogenesis.
Concerning the biology of LMO2-associated leukemia, we sought to correlate knowledge from mouse models of Lmo2-dependent leukemia with possible forced expression by way of retroviral insertion, as a stimulus for further experimentation. In the mouse models, Lmo2 expression is necessary but not sufficient for T-cell leukemia.3 Although the tumors can progress to the mature phenotype, this is not always the case, and more important, a post-thymic role is not necessary since leukemogenesis is identical in mice with or without RAG recombinase, meaning that T-cell leukemias can arise from immature cells without T-cell receptors.3
Finally, the information about the third patient with X-linked SCID with retroviral insertion into LMO2 is in fact in the public domain,4 quoted by one of Fischer's cosignatories. We do not imply that leukemia exists in this patient, but, rather, ask “whether the LMO2 gene is a preferred . . . target.” The observation by Dave and colleagues of a retrovirally induced T-cell leukemia in mice with insertions into both the LMO2 and IL2Rγc genes5 gives verisimilitude to this notion.
5 ReferencesTerence H. Rabbitts, Ph.D.
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United KingdomMatthew P. McCormack, Ph.D.
Rotary Bone Marrow Research Laboratory, Melbourne, Victoria 3050, Australia1
White H ,Thrasher A ,Veys P ,Kinnon C ,Gaspar HB . Intrinsic defects of B cell function in X-linked severe combined immunodeficiency. Eur J Immunol 2000;30:732-737
CrossRef | Web of Science | Medline2
Fry TJ ,Mackall CL . Interleukin-7: from bench to clinic. Blood 2002;99:3892-3904
CrossRef | Web of Science | Medline3
Rabbitts TH . Chromosomal translocation master genes, mouse models and experimental therapeutics. Oncogene 2001;20:5763-5777
CrossRef | Web of Science | Medline4
Check E . Cancer fears cast doubts on future of gene therapy. Nature 2003;421:678-678
CrossRef | Web of Science | Medline5
Dave UP ,Jenkins NA ,Copeland NG . Gene therapy insertional mutagenesis insights. Science 2004;303:333-333
CrossRef | Web of Science | Medline
- Citing Articles (22)
Citing Articles
1
Vijay G. Sankaran, David G. Nathan. (2010) Thalassemia: An Overview of 50 Years of Clinical Research. Hematology/Oncology Clinics of North America 24:6, 1005-1020
CrossRef2
Maria J. Marcaida, Inés G. Muñoz, Francisco J. Blanco, Jesús Prieto, Guillermo Montoya. (2010) Homing endonucleases: from basics to therapeutic applications. Cellular and Molecular Life Sciences 67:5, 727-748
CrossRef3
Derek A Persons, Arthur W Nienhuis. 2009. Haemoglobin Disorders: Gene Therapy. .
CrossRef4
Katrin Hacke, Rustom Falahati, Linda Flebbe-Rehwaldt, Noriyuki Kasahara, Karin M. L. Gaensler. (2009) Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation. Immunologic Research 44:1-3, 112-126
CrossRef5
Suk See De Ravin, Harry L. Malech. (2009) Partially corrected X-linked severe combined immunodeficiency: long-term problems and treatment options. Immunologic Research 43:1-3, 223-242
CrossRef6
Samuel L. Murphy, Katherine A. High. (2008) Gene therapy for haemophilia. British Journal of Haematology 140:5, 479-487
CrossRef7
Elodie Robert-Richard, François Moreau-Gaudry, Magalie Lalanne, Isabelle Lamrissi-Garcia, Muriel Cario-André, Véronique Guyonnet-Dupérat, Laurence Taine, Cécile Ged, Hubert de Verneuil. (2008) Effective Gene Therapy of Mice with Congenital Erythropoietic Porphyria Is Facilitated by a Survival Advantage of Corrected Erythroid Cells. The American Journal of Human Genetics 82:1, 113-124
CrossRef8
Javier Chinen, Fabio Candotti. 2008. Gene transfer therapy of immunologic diseases. , 1281-1292.
CrossRef9
Martin F Ryser, Joachim Roesler, Marcus Gentsch, Sebastian Brenner. (2007) Gene therapy for chronic granulomatous disease. Expert Opinion on Biological Therapy 7:12, 1799-1809
CrossRef10
Kumi Yoshida, Yoshikazu Yonemitsu, Sakura Tanaka, Shuro Yoshida, Satoko Shibata, Haruhiko Kondo, Shinji Okano, Fumihiko Ishikawa, Koichi Akashi, Makoto Inoue, Mamoru Hasegawa, Katsuo Sueishi. (2007) In vivo repopulation of cytoplasmically gene transferred hematopoietic cells by temperature-sensitive mutant of recombinant Sendai viral vector. Biochemical and Biophysical Research Communications 361:3, 811-816
CrossRef11
A. Capotondo, M. Cesani, S. Pepe, S. Fasano, S. Gregori, L. Tononi, M.A. Venneri, R. Brambilla, A. Quattrini, A. Ballabio, M.P. Cosma, L. Naldini, A. Biffi. (2007) Safety of Arylsulfatase A Overexpression for Gene Therapy of Metachromatic Leukodystrophy. Human Gene Therapy 18:9, 821-836
CrossRef12
Alessandra Biffi, Luigi Naldini. (2007) Novel candidate disease for gene therapy: metachromatic leukodystrophy. Expert Opinion on Biological Therapy 7:8, 1193-1205
CrossRef13
Elodie Robert-Richard, Emmanuel Richard, Punam Malik, Cécile Ged, Hubert de Verneuil, François Moreau-Gaudry. (2007) Murine Retroviral but not Human Cellular Promoters Induce In Vivo Erythroid-specific Deregulation that can be Partially Prevented by Insulators. Molecular Therapy 15:1, 173-182
CrossRef14
Alessandra Biffi, Alessia Capotondo, Stefania Fasano, Ubaldo del Carro, Sergio Marchesini, Hisaya Azuma, Maria Chiara Malaguti, Stefano Amadio, Riccardo Brambilla, Markus Grompe, Claudio Bordignon, Angelo Quattrini, Luigi Naldini. (2006) Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. Journal of Clinical Investigation 116:11, 3070-3082
CrossRef15
Claudio Bordignon. (2006) Stem-cell therapies for blood diseases. Nature 441:7097, 1100-1102
CrossRef16
ARTHUR BANK, RONALD DORAZIO, PHILIPPE LEBOULCH. (2005) A Phase I/II Clinical Trial of β-Globin Gene Therapy for β-Thalassemia. Annals of the New York Academy of Sciences 1054:1, 308-316
CrossRef17
Frederic Bushman, Mary Lewinski, Angela Ciuffi, Stephen Barr, Jeremy Leipzig, Sridhar Hannenhalli, Christian Hoffmann. (2005) Genome-wide analysis of retroviral DNA integration. Nature Reviews Microbiology 3:11, 848-858
CrossRef18
Alessandra Biffi, Luigi Naldini. (2005) Gene Therapy of Storage Disorders by Retroviral and Lentiviral Vectors. Human Gene Therapy 16:10, 1133-1142
CrossRef19
Alessandra Biffi, Luigi Naldini. (2005) Gene Therapy of Storage Disorders by Retroviral and Lentiviral Vectors. Human Gene Therapy 0:0, 050831054349001
CrossRef20
Alain Fischer, Francoise Le Deist, Salima Hacein-Bey-Abina, Isabelle Andre-Schmutz, Genevieve de Saint Basile, Jean-Pierre de Villartay, Marina Cavazzana-Calvo. (2005) Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunological Reviews 203:1, 98-109
CrossRef21
Marina Cavazzana-Calvo, Chantal Lagresle, Salima Hacein-Bey-Abina, Alain Fischer. (2005) Gene Therapy for Severe Combined Immunodeficiency. Annual Review of Medicine 56:1, 585-602
CrossRef22
Javier Chinen, Jennifer M Puck. (2004) Perspectives of gene therapy for primary immunodeficiencies. Current Opinion in Allergy and Clinical Immunology 4:6, 523-527
CrossRef
