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Alain Fischer - One of the best experts on this subject based on the ideXlab platform.
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gene therapy for severe Combined Immunodeficiencies and beyond
Journal of Experimental Medicine, 2020Co-Authors: Alain Fischer, Salima HaceinbeyabinaAbstract:Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.
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A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe Combined immunodeficiency
Haematologica, 2020Co-Authors: Chantal Lagresle-peyrou, Alain Fischer, Despina Moshous, Aurélien Olichon, Hanem Sadek, Philippe Roche, Claudine Tardy, Cindy Da Silva, Alexandrine Garrigue, Yves ColletteAbstract:Severe Combined Immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.
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Severe Combined Immunodeficiencies and related disorders
Nature Reviews Disease Primers, 2015Co-Authors: Alain Fischer, Bénédicte Neven, Luigi D. Notarangelo, Marina Cavazzana, Jennifer M. PuckAbstract:Severe Combined Immunodeficiencies comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in T lymphocyte development. In this Primer, Fischer and colleagues explain the pathogenesis of this disorder with a focus on current and future treatment strategies. Severe Combined Immunodeficiencies (SCIDs) comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in the development of T lymphocytes. Given that adaptive immunity is abrogated, patients with SCID are prone to recurrent infections caused by both non-opportunistic and opportunistic pathogens, leading to early death unless immunity can be restored. Several molecular defects causing SCIDs have been identified, along with many other defects causing profound, albeit incomplete, T cell Immunodeficiencies; the latter are referred to as atypical SCIDs or Combined Immunodeficiencies. The pathophysiology of many of these conditions has now been characterized. Early, accurate and precise diagnosis Combined with the ongoing implementation of newborn screening have enabled major advances in the care of infants with SCID, including better outcomes of allogeneic haematopoietic stem cell transplantation. Gene therapy is also becoming an effective option. Further advances and a progressive extension of the indications for gene therapy can be expected in the future. The assessment of long-term outcomes of patients with SCID is now a major challenge, with a view to evaluating the quality and sustainability of immune restoration, the risks of sequelae and the ability to relieve the non-haematopoietic syndromic manifestations that accompany some of these conditions.
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severe Combined Immunodeficiencies and related disorders
Nature reviews. Disease primers, 2015Co-Authors: Alain Fischer, Bénédicte Neven, Luigi D. Notarangelo, Marina Cavazzana, Jennifer M. PuckAbstract:Severe Combined Immunodeficiencies (SCIDs) comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in the development of T lymphocytes. Given that adaptive immunity is abrogated, patients with SCID are prone to recurrent infections caused by both non-opportunistic and opportunistic pathogens, leading to early death unless immunity can be restored. Several molecular defects causing SCIDs have been identified, along with many other defects causing profound, albeit incomplete, T cell Immunodeficiencies; the latter are referred to as atypical SCIDs or Combined Immunodeficiencies. The pathophysiology of many of these conditions has now been characterized. Early, accurate and precise diagnosis Combined with the ongoing implementation of newborn screening have enabled major advances in the care of infants with SCID, including better outcomes of allogeneic haematopoietic stem cell transplantation. Gene therapy is also becoming an effective option. Further advances and a progressive extension of the indications for gene therapy can be expected in the future. The assessment of long-term outcomes of patients with SCID is now a major challenge, with a view to evaluating the quality and sustainability of immune restoration, the risks of sequelae and the ability to relieve the non-haematopoietic syndromic manifestations that accompany some of these conditions.
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Gene therapy of primary T cell Immunodeficiencies.
Gene, 2013Co-Authors: Alain Fischer, Salima Hacein-bey-abina, Marina Cavazzana-calvoAbstract:Gene therapy of severe Combined Immunodeficiencies has been proven to be effective to provide sustained correction of the T cell Immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (γc deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary Immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative.
Andrea Gangfuß - One of the best experts on this subject based on the ideXlab platform.
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Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie
Journal of Clinical Immunology, 2020Co-Authors: Sonu Shai, Ruy Perez-becker, Oliver Andres, Shahrzad Bakhtiar, Ulrich Bauman, Horst Bernuth, Carl-friedrich Classen, Gregor Dückers, Sabine M. El-helou, Andrea GangfußAbstract:Purpose Severe Combined Immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. Methods The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). Results Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. Conclusions SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
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Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie
Journal of Clinical Immunology, 2020Co-Authors: Sonu Shai, Ruy Perez-becker, Oliver Andres, Shahrzad Bakhtiar, Ulrich Bauman, Horst Bernuth, Carl-friedrich Classen, Gregor Dückers, Sabine M. El-helou, Andrea GangfußAbstract:Purpose Severe Combined Immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. Methods The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). Results Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. Conclusions SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
Adrian J Thrasher - One of the best experts on this subject based on the ideXlab platform.
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gene therapy for severe Combined Immunodeficiencies
Expert Opinion on Biological Therapy, 2005Co-Authors: Bobby H Gaspar, Adrian J ThrasherAbstract:Severe Combined immune deficiencies (SCIDs) are a group of monogenic diseases resulting in profound disturbances of lymphocyte development and function. Affected individuals are prone to life-threatening infections and without treatment do not survive beyond the first year of life. Haematopoietic stem cell transplantation from a well-matched donor offers high rates of survival, but in the absence of a suitable matched donor, parental haploidentical transplants are associated with greater complications, lower success rates and in some instances poor long-term immune recovery. Alternative therapeutic options based on correction of the defective gene by retroviral gene delivery have been used to correct X-linked SCID (SCID-X1) and adenosine deaminase-deficient SCID (ADA-SCID). A number of clinical trials have established that ex vivo gene transfer into haematopoietic progenitor cells allows effective recovery of immune defects and that gene therapy can offer a successful alternative to transplantation. The development of leukaemia as a result of insertional mutagenesis in one trial of gene therapy for SCID-X1 has raised concerns regarding the toxicity of retroviral vector-based gene delivery. These side effects are now being studied in detail and measures to prevent such events through alternative vectors delivery systems are in development at present.
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Gene therapy progress and prospects: gene therapy for severe Combined immunodeficiency
Gene Therapy, 2003Co-Authors: H B Gaspar, S Howe, Adrian J ThrasherAbstract:Severe Combined Immunodeficiencies have long been targeted as a group of disorders amenable to gene therapy because of their defined molecular biology and pathophysiology, and the prediction that corrected cells would have profound growth and survival advantage. Recently, several clinical studies have shown that conventional gene transfer technology can produce major beneficial therapeutic effects in these patients, but, as for all cellular and pharmacological treatment approaches, with a finite potential for toxicity.
Sonu Shai - One of the best experts on this subject based on the ideXlab platform.
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Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie
Journal of Clinical Immunology, 2020Co-Authors: Sonu Shai, Ruy Perez-becker, Oliver Andres, Shahrzad Bakhtiar, Ulrich Bauman, Horst Bernuth, Carl-friedrich Classen, Gregor Dückers, Sabine M. El-helou, Andrea GangfußAbstract:Purpose Severe Combined Immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. Methods The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). Results Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. Conclusions SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
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Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie
Journal of Clinical Immunology, 2020Co-Authors: Sonu Shai, Ruy Perez-becker, Oliver Andres, Shahrzad Bakhtiar, Ulrich Bauman, Horst Bernuth, Carl-friedrich Classen, Gregor Dückers, Sabine M. El-helou, Andrea GangfußAbstract:Purpose Severe Combined Immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. Methods The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). Results Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. Conclusions SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
Marina Cavazzanacalvo - One of the best experts on this subject based on the ideXlab platform.
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severe Combined immunodeficiency a model disease for molecular immunology and therapy
Immunological Reviews, 2005Co-Authors: Alain Fischer, Isabelle Andreschmutz, Francoise Le Deist, Jean-pierre De Villartay, Geneviève De Saint Basile, Salima Haceinbeyabina, Marina CavazzanacalvoAbstract:Summary: Severe Combined Immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.
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haploidentical allogeneic versus gene modified autologous stem cell transplantation for severe Combined Immunodeficiencies s c i d the risk benefit balance is in favor of gene therapy
Blood, 2004Co-Authors: Marina Cavazzanacalvo, Francoise Le Deist, Salima Haceinbeyabina, Genevieve De Saintbasile, Nicolas Wulfraat, Ian E Alexander, Paul Landais, Stephane Blanche, Alain FischerAbstract:For the last 35 years or so, allogeneic hematopoietic stem cell transplantation (HSCT) has been the only curative approach for patients affected by severe Combined Immunodeficiencies (SCID), a medical emergency. According to the most recent European survey haploidentical transplants allow a survival rate at 3 years of 75% (taking only into account patients transplanted since 1995). The mortality rate is heavily influenced by age at transplantation (being very low within young infants), in correlation with the infection burden and also the incidence of acute graft-versus-host reaction (GVHD). Between 1998 and 2003, 6 patients with NK(−) B(+) SCIDs (either gc or JAK3 deficiency) received an haploidentical HSCT at Necker Hospital, 3 of them died from an infection, one in the context of a severe GVHD. In addition, despite the improvement in the survival rate, over the time a number of long-term concerns have been detected including a frequent persistence of a B cell deficiency, and a decline in T-cell functions related to the absence of donor stem cell engraftment and may be also to a premature decline in the thymus function. Therefore, several patients have received a second transplant with a low efficiency in an haploidentical setting. These significant limitations set the rationale for the development of an alternative strategy such as gene therapy. From March 1999 up to May 2002, ten children with gc deficiency under the age of one year were enrolled. All of them are alive today. The gc gene transfer into patients’ CD34(+) cells led in 9 out of 10 patients to the emergence of T and NK lymphocytes. It took 10 to 12 weeks to detect mature T cells in the periphery, a delay which is significantly faster than the one observed after haploidentical HSCT. In all but 2 patients, T cell counts normalized up to 5.3 years after gene therapy. The occurrence of two severe adverse events led to put transiently the trial on hold in order to understand the pathophysiology of these events and assess its overall risks. Following a thorough analysis of the retrospective data and a prospective analysis, it was concluded that the benefit/risk balance in favor of the gene therapy approach at least for patients older than 3 months, hence our gene therapy protocol has been reopened. An update of the clinical data will provided at the meeting.
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gene therapy for human severe Combined Immunodeficiencies
Immunity, 2001Co-Authors: Alain Fischer, Francoise Le Deist, Geneviève De Saint Basile, Salima Haceinbey, Marina CavazzanacalvoAbstract:Besides long-term analysis of treated cases, there is an obvious need to reproduce these results in a larger set of patients, including more cases in whom an endogenous abnormal γc protein is present in lymphocyte precursors as well as patients with partially preserved T cell development (Notarangelo et al., 2000xNotarangelo, L.D., Giliani, S., Mazza, C., Mella, P., Savoldi, G., Rodriguez-Perez, C., Mazzolari, E., Fiorini, M., Duse, M., Plebani, A. et al. Immunol. Rev. 2000; 178: 39–48Crossref | PubMedSee all References(Notarangelo et al., 2000). Also, and this is not a straightforward issue, methods for the large-scale production of clinical batches of vectors have to be developed. What about extension to the treatment of other Immunodeficiencies? If one assumes that the most suitable disease was chosen, then treatment of other conditions raises additional difficulties (for a detailed discussion of the latter, see Candotti 2000xCandotti, F. Pediatr. Clin. North Am. 2000; 47: 1389–1407Abstract | Full Text | Full Text PDF | PubMedSee all References, Fischer et al. 2000xFischer, A., Hacein-Bey, S., Le Deist, F., Soudais, C., and Di Santo, J. Immunol. Rev. 2000; 178: 13–20Crossref | PubMedSee all References). This means that further advances in gene transfer technology in hematopoietic precursor cells will be necessary in this setting. Note, however, that for the treatment of conditions for which a selective advantage of transduced cells is expected, a high rate of CD34 (+) cell transduction might not be appropriate since: (1) a high rate of transduction is not necessary to achieve T lymphocyte development and (2) it will lead to the multiplication of the number of transgene copy integrations. The latter could potentially increase the risk of deleterious consequences of insertional mutagenesis. SCID conditions with an identical or closely related disease mechanism to SCID-X1, i.e., JAK-3 and IL-7Rα deficiency, are the most obvious next candidate diseases for gene therapy. Experimental gene therapy of JAK-3(-) mice has provided convincing results including proven efficacy in unirradiated mice (Bunting et al., 2000xBunting, K.D., Lu, T., Kelly, P.F., and Sorrentino, B.P. Hum. Gene Ther. 2000; 11: 2353–2364Crossref | PubMed | Scopus (33)See all References(Bunting et al., 2000). SCID conditions caused by Rag-1, Rag-2, or Artemis gene mutations are also worthwhile to consider, since allogeneic stem cell transplantation provides poorer results than for other SCID conditions. Genetic deficiencies in the immune system that impair further downstream T cell development will be more difficult to tackle since (1) a less potent selective advantage is to be expected and (2) considerations on transgene expression regulation (both spatial and temporal) will have to be addressed. In this respect however, the spectacular achievement of tissue-specific β-globin expression in erythroid cells in β thalassemic mice represents a significant advance. This result is based on the insertion in the lentiviral vector of a minimal version of the locus control region (LTR) of the β-globin gene (May et al., 2000xMay, C., Rivella, S., Callegari, J., Heller, G., Gaensler, K.M., Luzzatto, L., and Sadelain, M. Nature. 2000; 406: 82–86Crossref | PubMed | Scopus (372)See all References(May et al., 2000).One can, from the above, consider that proof of principle has been achieved in the genetic treatment of inherited disorders of the immune system. Much remains to be done by combining both an in depth appraisal of every single disease mechanism (i.e., in other words, understanding the function of the corresponding gene product) and development of new aspects in gene transfer technologies. It is obvious that a potentially safe use of lentiviral vectors able to efficiently target HSC would provide a major advance to the field (reviewed in Sadelain et al., 2000xSadelain, M., Frassoni, F., and Riviere, I. Curr. Opin. Hematol. 2000; 7: 364–377Crossref | PubMed | Scopus (20)See all ReferencesSadelain et al., 2000). Technologies of gene repair might also become a consideration in the future.
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gene therapy of severe Combined Immunodeficiencies
Immunological Reviews, 2000Co-Authors: Alain Fischer, Francoise Le Deist, Geneviève De Saint Basile, Claire Soudais, Salima Haceinbey, James P Di Santo, Marina CavazzanacalvoAbstract:Primary immunodeficiency diseases (PID) are attractive candi dates for a gene therapy approach because many of these disorders convey a poor prognosis while a number of the genes mutated in these conditions have been identified. Gene transfer into hematopoietic stem cells (HSC) should, in theory, lead to a cure of the disease. There are, however, a number of limitations mostly related to the failure of clinically available vectors to enable transgene integration into HSC. Nevertheless PID due to a gene defect leading to failure of cell development could be amenable to gene therapy given the selective advantage conferred to transgene expression in progenitor cells. Terminally differentiated cells are, however, long lived, as is the case for T lymphocytes. This concept led to the first gene therapy trials for adenosine deaminase (ADA) deficiency several years ago. Results were in part disappointing mostly because of the concomitant substitutive treatment by polyethylene glycol-ADA. However, recent application to X-linked severe Combined immunodeficiency (gamma(c) deficiency) turned out to be efficient at least on a relatively short term basis (i.e. one year so far). These results demonstrate that this concept is valid and can be the basis for the treatment of other forms of severe T-cell Immunodeficiencies. Obviously, development of vectors (lentiviruses) able to efficiently target HSC could in the future considerably enlarge the field of PID treatable by gene transfer.