SEARCH:   Advanced

Blood, 1 June 2005, Vol. 105, No. 11, pp. 4160-4161. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Seggewiss, R. Articles by Dunbar, C. E. Search for Related Content PubMed Articles by Seggewiss, R. Articles by Dunbar, C. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Comment on Thrasher et al, page 4255 Old before its time: age-related thymic dysfunction may preclude efficacy of gene therapy in older SCID-X1 patients Ruth Seggewiss, and Cynthia E. Dunbar NATIONAL HEART, LUNG, AND BLOOD INSTITUTE Gene therapy can not be reserved as a "salvage therapy" in SCID-X1 patients failing bone marrow transplantation. Thrasher and colleagues report in this issue of Blood on the failure of gene therapy to correct immune function when attempted in 2 patients aged 15 and 20 years with X-linked severe combined immunodeficiency (SCID-X1). Besides the implications for the timing of gene therapy, the study also further demonstrates the rapid and irreversible aging of the thymus, and highlights the difficulties of completely recreating an immune system beyond early childhood. Children with severe forms of SCID, in particular SCID-X1, usually die at less than 1 year of age from opportunistic infections. Long-term survival is possible only with allogeneic stem cell transplantation (SCT), but delayed diagnosis can result in severe infections that preclude successful transplantation.1 Even with early allogeneic transplantation, in particular with haploidentical parental donors, there is incomplete engraftment, with progressive defects in T-cell immunity and a complete lack of donor B cells, resulting in dependency on monthly intravenous infusions of immunoglobulin. These poor outcomes stimulated intense interest in gene therapy approaches to SCID. In about 50% of all cases, SCID is inherited as an X-linked recessive disease characterized by a block in T and natural killer (NK) lymphocyte differentiation. The defective gene encodes the common cytokine receptor -chain, located on the X chromosome. The report of complete immune correction of young SCID-X1 boys by transduction of their CD34+ bone marrow cells with a retroviral vector encoding the common -chain, and reinfusion of transduced cells without conditioning therapy, was very encouraging and represented the first unequivocal demonstration of gene therapy efficacy.2,3 However, worryingly, 2 children in this trial developed T-cell leukemia due to insertion of the retroviral vector near the promoter of the proto-oncogene LMO2,4 and a third child out of a total of 11 entered in the trial was recently also reported to have T-cell leukemia. Thus, at present the risks and potential benefits of gene therapy for this disease are being reconsidered. Thrasher and colleagues now report the failure of gene therapy to produce therapeutic effects and T-cell reconstitution despite successful CD34+ cell transduction in 2 patients with SCID-X1 aged 15 and 20 years, both enrolled in the trial at these advanced ages due to gradual failure of immune function following bone marrow transplantation (BMT). Whether the apparent impossibility for productive thymopoiesis in these patients was the result of previous infections, graft-versus-host disease (GVHD), or physiological aging of the thymus remains hypothetical. It mirrors the observed correlation between patient age at the time of BMT and poor immune outcome in SCID-X1 (eg, Patel et al5). This is a very important finding regarding the current discussion about the optimal treatment strategy in the absence of human leukocyte antigen (HLA)–matched donors for SCID-X1 patients. It appears that gene therapy can not be reserved as a "salvage therapy" in SCID-X1 patients failing or not maintaining immune function following BMT. There is a need to compare the oncogenic potential of different vectors in relevant animal models in order to develop safer gene therapy approaches based on their potential for insertional activation of oncogenes, but, as the work of Thrasher and colleagues demonstrates, additional efforts are also required to better understand the biology of diseases that are candidates for therapeutic genetic intervention to design optimal treatment strategies. References Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997;130: 378-387.[CrossRef][Medline] [Order article via Infotrieve] Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288: 669-672.[Abstract/Free Full Text] Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002;346: 1185-1193.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] Patel DD, Gooding ME, Parrott RE, Curtis KM, Haynes BF, Buckley RH. Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 2000;342: 1325-1332.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Failure of SCID-X1 gene therapy in older patients Adrian J. Thrasher, Salima Hacein-Bey-Abina, H. Bobby Gaspar, Stephane Blanche, E. Graham Davies, Kathryn Parsley, Kimberly Gilmour, Douglas King, Steven Howe, Joanna Sinclair, Christophe Hue, Frédérique Carlier, Christof von Kalle, Geneviève de Saint Basile, Françoise le Deist, Alain Fischer, and Marina Cavazzana-Calvo Blood 2005 105: 4255-4257. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Seggewiss, R. Articles by Dunbar, C. E. Search for Related Content PubMed Articles by Seggewiss, R. Articles by Dunbar, C. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020