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101. Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center

Author

Ozsahin, H., Le Deist, F., Benkerrou, M., Cavazzana-Calvo, M., Gomez, L., Griscelli, C., Blanche, S., and Fischer, A.

Abstract

We retrospectively analyzed the outcome of bone marrow transplantation (BMT) performed in 26 patients with Wiskott- Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-1 and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced B-lymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS. (J PEDIATR 1996;129:238-44)

Published
1996
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102. γcGene Transfer Into SCID X1 Patients’ B-Cell Lines Restores Normal High-Affinity Interleukin-2 Receptor Expression and Function

Author

Hacein-Bey, S., Cavazzana-Calvo, M., Deist, F.Le, Dautry-Varsat, A., Hivroz, C., Rivière, I., Danos, O., Heard, J.M., Sugamura, K., Fischer, A., and Basile, G.De Saint

Abstract

SCID X1 is characterized by faulty T-cell and natural killer cell differentiation caused by mutation of the γcchain gene encoding a number of multiple cytokine receptors (interleukin-2 [IL-2], IL-4, IL-7, IL-9, and IL-15 receptors). To assess the feasibility of inducing long-term expression and function of the γcchain, Epstein-Barr virus (EBV)-transformed B-cell lines from two patients with SCID X1 were transduced with a Moloney-derived retroviral vector containing the γcchain cDNA. The viral LTR was used as the promoter. Immediately after two cycles of coculture with the Pcrip clone producing the MFG(B2)-γccDNA vector, γcexpression, assessed by detection of the mRNA and membrane protein expression, was found in 15% to 20% of cells. The degree of membrane expression was similar to that in control EBV-B cells. Expression increased steadily over 6 months, becoming detectable in 100% of cells, and remained stable thereafter for a total of 9 months, reflecting positive selection of transduced cells. A study of provirus integration sites showed multiple integration. The expressed γcwas functional, because it restored high-affinity IL-2 receptor binding, IL-2 endocytosis, and IL-2–triggered phosphorylation of JAK-3 tyrosine kinase. Similar results were obtained with the two B-cell lines. These results show that efficient γcgene transfer into B-cells lacking functional γcis feasible and results in strong and stable expression of a functional γcchain, apparently conferring a selective growth advantage in culture. Further in vitro studies of γcgene transfer into γc-hematopoietic progenitors are being conducted to assess the feasibility of correcting lymphocyte differentiation defects.

Published
1996
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103. Prévention du rejet d'allogreffe intestinale par des anticorps antimolécules d'adhésion dans un modèle murin

Author

Auber, F, Cerf-Bensussan, N, Cavazzana-Calvo, M, Fauveau, V, Brousse, N, Fischer, A, Révillon, Y, and Sarnacki, S

Abstract

Study aimSmall bowel transplantation is still hampered by a high morbidity and mortality linked to the heavy non specific immunosuppression which is required by the transplantation of this lymphoid organ. Adhesion molecules appear to be potential targets for specific immunosuppression. The aim of the study was to investigate the effect of a transitory administration of anti-LFA-1 or anti-α4 monoclonal antibodies (mAb) in the prevention of rejection in a model of fetal small-bowel transplantation in mice.Materials and methodsThe small bowel of C57BL/6 (H-2b) fetus (16 to 20 days of gestation) was transplanted into adult C3H/He mice (H-2k) or C57BL/6 recipient mice. Recipients were treated with a short course of either antiLFA-1 mAb alone, either with anti-α4 mAb alone, or with both mAb. Biopsies with histological study of the grafts were performed between post-operative day 5 and 60. A score of development and rejection was assigned to each sample.ResultsNormal intestinal development with no sign of rejection was observed in 24/28 syngenic grafts till postoperative day 45. In the absence of treatment, intense rejection was observed as soon as day 5 and all allogenic grafts were rejected (n=22). In contrast, in anti-LFA-1 mAb treated mice, 18/20 allogenic grafts developed normally with minimal signs of rejection. In anti-α4 treated mice, a transient protective effect on small bowel allograft survival was observed on day 7 but thereafter, all grafts were massively rejected within a few days (n = 18). The combination of both mAb didn't improve the survival of the grafts when compared to anti-LFA-1 mAb treated grafts (n = 10).ConclusionThese results demonstrate that a transitory administration of anti-LFA-1 mAb, but not of anti-α4 mAb, is able to prolong significantly the survival of non vascularized small bowel fetal grafts in mice. Our results are promising for the possible use of the anti-LFA-1 mAb in clinical intestinal transplantation.

Published
1998
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104. Role of Interleukin-2 (IL-2), IL-7, and IL-15 in Natural Killer Cell Differentiation From Cord Blood Hematopoietic Progenitor Cells and From γc Transduced Severe Combined Immunodeficiency X1 Bone Marrow Cells

Author

Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., De Coene, C., Selz, F., Le Deist, F., and Fischer, A.

Abstract

Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodefiency (SCID X1) carry mutations in the γc cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share γc receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood CD34 (+) cells in the presence of either stem cell factor (SCF), IL-2, and IL-7 or SCF and IL-15. The former cytokine combination efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following ret-roviral-mediated gene transfer of γc into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the γc chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with γc is involved in this process at an earlier step than IL-2/IL-7 interactions of γc are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.

Published
1996
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107. [T-cell-depleted HLA non-identical bone marrow transplantation in the child: prevention of graft-versus-host reaction by administration of donor T lymphocytes alloreactive against the recipient]

Author

Cavazzana-Calvo M, Isabelle André, Hacein-Bey S, Schindler J, Vitetta H, Dupuis S, Quartier P, Chedeville G, Vilmer E, Jl, Casanova, Buffet R, Caillat-Zucman S, Radford I, Le Deist F, and Fischer A

Subjects
Immunotoxins, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, Infant, Newborn, Antibodies, Monoclonal, Graft vs Host Disease, Infant, Receptors, Interleukin-2, Infections, Lymphocyte Depletion, Treatment Outcome, T-Lymphocyte Subsets, Child, Preschool, Hematologic Neoplasms, Histocompatibility, Acute Disease, Humans, Transplantation, Homologous, Lymphocyte Count, Lymphocyte Culture Test, Mixed, Child
Abstract

The success of HSCT from HLA partially disparate donors depends on the development of new strategies able to efficiently prevent GVHD and to protect patients from infections and relapse. Using an immunotoxin (IT) directed against the alpha-chain (p55) of the human IL-2r (RFT5-SMPT-dgA), we have previously shown that it is possible to kill mature T cells activated towards a specific HLA complex by a one-way MLR. We designed a clinical trial assessing the effect of infusing increasing doses of T lymphocytes in the setting of children recipients of non HLA genetically identical HSCT. Thirteen patients have been enrolled from September 1998 to April 2000 and fourteen HSCT have been realized in 13 patients (pts). Donors were MUD in 3 cases and familial HLA partially disparate in the remaining cases. Allodepleted donor T cells were injected between day +14 and day +30 provided that ATG was undetectable in the serum and blood PMN counts was500/microliter. The mean age of these patients was 17 months (range 1 to 42). Diagnosis included immune deficient and malignant hemopathies. Three patients received 1 x 10(5) allodepleted T cell/kg, 7 patients received 4 x 10(5)/kg and 4 patients received 6 x 10(5)/kg allodepleted T cells. Full inhibition of MLR was achieved in 12 out of 14 cases. In two cases, a residual T cell reactivity to the recipient was observed (4 to 5%) and patients developed grade II aGVHD. aGVHD occurred in 4 out of 11 grafted patients (all grade II). No chronic GVHD has developed, so far. Three patients died from severe VOD or PHT at day +34, day 51 and day +166, while one infected patient by VZV, CMV and EBV before HSCT died 6 months after transplantation from meningoencephalitis and another patient died from relapse at day +291. The patient for which there was no engraftment died at day +48 from staphylococcus infection. Overall survival is 54%, with a median follow up of 8 months; the mean time to reach a blood lymphocyte count500 was 41 days, to reach a CD3 count300 microliters 63 days (20-111), CD4200 microliters 97 days and positive mitogen-induced proliferation 90 days. In three patients, a tetanus-toxoid positive proliferation was detected before immunization. From this intermediate analysis, we conclude that 1) specific allodepletion is an effective approach to prevent aGVHD in a haploincompatible setting, 2) data on immunological reconstitution suggest that infused T cells do survive and expand. A higher number of patients must be enrolled to determine the optimal number of T cells to infuse.

108. Gene therapy of primary immunodeficiencies

Author

Fischer A, Genevieve de Saint Basile, Jp, Disanto, Hacein-Bey S, Sharara L, and Cavazzana-Calvo M

Subjects
Phagocytes, Adenosine Deaminase, Bone Marrow, T-Lymphocytes, Immunologic Deficiency Syndromes, Leukocytes, Humans, Severe Combined Immunodeficiency, Genetic Therapy, Hematopoietic Stem Cells

109. [Gene therapy of severe combined immunodeficiencies]

Author

Cavazzana-Calvo M, Hacein-Bey S, Genevieve de Saint Basile, Le Deist F, and Fischer A

Subjects
X Chromosome, Genetic Linkage, T-Lymphocytes, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Infant, Receptors, Interleukin, Genetic Therapy, Mice, SCID, Killer Cells, Natural, Mice, T-Lymphocyte Subsets, Mutation, Animals, Humans, Severe Combined Immunodeficiency

110. [Gene therapy for immune deficiencies]

Author

Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, jeanpierre de villartay, and Cavazzana-Calvo M

Subjects
Immunologic Deficiency Syndromes, Humans, Genetic Therapy
Abstract

Gene therapy offers an attractive option to the most severe forms of primary immunodeficiency diseases. Identification of disease associated genes as well as advances in the technology of gene transfer into hematopoietic progenitor cells have set the basis for the first clinical trials. Settings characterized by the potential for a selective advantage provided to transduced cells are the first diseases to target. The recent example of successful treatment of Severe Combined Immunodeficiency-X1 (gamma c deficiency) illustrates this potential.

114. Long-term immune reconstitution and outcome after HLA-nonidentical T- cell-depleted bone marrow transplantation for severe combined immunodeficiency: A European retrospective study of 116 patients

Author

Elie Haddad, Landais, P., Friedrich, W., Gerritsen, B., Cavazzana-Calvo, M., Morgan, G., Bertrand, Y., Fasth, A., Porta, F., Cant, A., Espanol, T., Müller, S., Veys, P., Vossen, J., and Fischer, A.

Subjects
B-Lymphocytes, Transplantation Conditioning, T-Lymphocytes, Remission Induction, Graft vs Host Disease, Survival Analysis, Lymphocyte Depletion, Cohort Studies, Europe, Treatment Outcome, Virus Diseases, Humans, Transplantation, Homologous, Severe Combined Immunodeficiency, Lymphocyte Count, Bone Marrow Transplantation, Retrospective Studies
Abstract

We have performed a retrospective analysis of the development of T- and B-cell functions after HLA-nonidentical T-cell-depleted bone marrow transplantation (BMT) performed in 193 patients with severe combined immunodeficiency (SCID) at 18 European centers between December 1982 and December 31, 1993. One hundred sixteen of 193 patients were alive with evidence of engraftment 6 months after BMT. Development of T-cell function occurred earlier than B-cell function and was achieved more frequently up to the time of last follow-up. The median time to achieve normal T-cell function was 8.7 months, whereas the median time to achieve normal B-cell function was 14.9 months. Twenty-four patients died later than 6 months post-BMT, mainly due to chronic graft-versus-host disease (cGVHD) and/or viral infection. Absence of T-cell reconstitution 6 months after BMT, unlike absence of B-cell reconstitution, was associated with a poor outcome. Two additional factors were associated with a poor outcome: presence of cGVHD 6 months after BMT and B- SCID versus B+ SCID. However, two of these three factors remained as significant prognostic factors in a multivariate analysis: the absence of T-cell function and the presence of cGVHD 6 months after BMT. Analysis of the factors influencing the development of immune reconstitution showed that T- and B-cell functions occurred earlier and more frequently in B+ SCID versus B- SCID patients. Acute GVHD was associated with a slower development of T-cell function at 6 months, and cGVHD had a negative influence on the development of T-cell function afterwards, but neither acute nor chronic GVHD was found to influence the development of B-cell function. Once engraftment occurred, whether patients had or had not received Busulfan in the conditioning regimen did not influence the kinetics and quality of T-cell function development. In a multivariate study, two factors were found to influence the T-cell function 6 months after BMT: type of SCID and acute GVHD. The results of this retrospective analysis should lead to new protocols adapted to SCID disease, considering that disease-related as well as BMT-related parameters influence the development of immune function and thereby long-term outcome after HLA-nonidentical T-cell-depleted BMT.

116. [The bone marrow: a reserve of stem cells able to repair various tissues?]

Author

Cavazzana-Calvo M, Lagresle C, Isabelle André, and Hacein-Bey-Abina S

Subjects
Stem Cells, Animals, Humans, Antigens, CD34, Bone Marrow Cells, Hematopoietic Stem Cells, Cell Division, Bone Marrow Transplantation
Abstract

Hematopoietic stem cells (HSC) have been widely used for autologous and allodeneic transplantation during decades, although little was known about their migration, survival, self-renewal and differentiation process. Their sorting by the CD34(+) marker they express at the cell surface in human has been challenged by the recent discovery of HSC in the CD34(-) compartment that may precede CD34(+) HSC in the differentiation process. Until recently, stem cells present in the bone marrow were thought to be specific for hematopoiesis. Some experiments including clinical trials showing the formation of various tissues, muscle, neural cells and hepatocytes for instance, after transplantation of medullar cells, have challenged this dogma. In fact, the proofs of such a transdifferentiation process by HSC are still missing and the observations may result from the differentiation of other mulipotent stem cells present in the bone marrow, such as mesenchymal stem cells and more primitive multipotent adult progenitor cells (MAPC) and side population (SP) cells.

120. Selective allodepletion.

Author

Cavazzana-Calvo, M. and André-Schmutz, I.

Subjects
*STEM cells, *HEMATOPOIETIC stem cells, *BONE marrow cells, *TRANSPLANTATION of organs, tissues, etc., *GRAFT rejection, *VIRUS diseases
Abstract

The article informs that GvHD, which was the main limitation of allogeneic hematopoietic stem cell transplantation (HSCT), has been almost completely eliminated by extensive depletion of donor T cells from the graft combined with profound immunosuppressive treatment. However, the consequence of these non-specific strategies is a long-lasting immunodeficiency associated with increased incidence of disease relapse, graft rejection and reactivation of viral infections. It informs that over the last 10-15 years a number of research teams in Europe and North America have worked out various alloselective approaches from first principles, through translational research to clinical trials.

Published
2005
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123. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe.

Author

Ljungman, P., Urbano-Ispizua, A., Cavazzana-Calvo, M., Demirer, T., Dini, G., Einsele, H., Gratwohl, A., Madrigal, A., Niederwieser, D., Passweg, J., Rocha, V., Saccardi, R., Schouten, H., Schmitz, N., Socie, G., Sureda, A., and Apperley, J.

Subjects
*GRAFT versus host disease, *BONE marrow transplant complications, *HEMATOPOIETIC stem cells, *AUTOGRAFTS, *HEMATOPOIETIC stem cell transplantation, *BLOOD diseases, *IMMUNOLOGIC diseases
Abstract

The Accreditation Subcommittee of the EBMT regularly publishes special reports on current practice of haemopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published in 1996. Haemopoietic stem cell transplantation today includes grafting with allogeneic and autologous stem cells derived from bone marrow, peripheral blood and cord blood. With reduced intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged such as autoimmune disorders and AL amyloidosis for autologous, and solid tumours for allogeneic transplants. The introduction of alternative therapies has challenged well-established indications such as imatinib for chronic myeloid leukaemia. An updated report with revised tables and operating definitions is presented here.Bone Marrow Transplantation (2006) 37, 439–449. doi:10.1038/sj.bmt.1705265; published online 30 January 2006 [ABSTRACT FROM AUTHOR]

Published
2006
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125. Critical Variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency.

Author

van der Loo, J C M, Swaney, W P, Grassman, E, Terwilliger, A, Higashimoto, T, Schambach, A, Hacein-Bey-Abina, S, Nordling, D L, Cavazzana-Calvo, M, Thrasher, A J, Williams, D A, Reeves, L, and Malik, P

Subjects
*IMMUNOLOGICAL deficiency syndromes, *GENE therapy, *GENE expression, *INTERLEUKIN-2, *ONCOGENES, *CLINICAL trials, *ENZYME activation, *LABORATORY mice, *PATIENTS
Abstract

Patients with X-linked severe combined immunodeficiency (SCID-X1) were successfully cured following gene therapy with a gamma-retroviral vector (gRV) expressing the common gamma chain of the interleukin-2 receptor (IL2RG). However, 5 of 20 patients developed leukemia from activation of cellular proto-oncogenes by viral enhancers in the long-terminal repeats (LTR) of the integrated vector. These events prompted the design of a gRV vector with self-inactivating (SIN) LTRs to enhance vector safety. Herein we report on the production of a clinical-grade SIN IL2RG gRV pseudotyped with the Gibbon Ape Leukemia Virus envelope for a new gene therapy trial for SCID-X1, and highlight variables that were found to be critical for transfection-based large-scale SIN gRV production. Successful clinical production required careful selection of culture medium without pre-added glutamine, reduced exposure of packaging cells to cell-dissociation enzyme, and presence of cations in wash buffer. The clinical vector was high titer; transduced 68-70% normal human CD34+ cells, as determined by colony-forming unit assays and by xenotransplantation in immunodeficient NOD.CB17-Prkdcscid/J (nonobese diabetic/severe combined immunodeficiency (NOD/SCID)) and NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NOD/SCID gamma (NSG))) mice; and resulted in the production of T cells in vitro from human SCID-X1 CD34+ cells. The vector was certified and released for the treatment of SCID-X1 in a multi-center international phase I/II trial. [ABSTRACT FROM AUTHOR]

Published
2012
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126. Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer.

Author

Pike-Overzet, K., Rodijk, M., Ng, Y.-Y., Baert, M. R. M., Lagresle-Peyrou, C., Schambach, A., Zhang, F., Hoeben, R. C., Hacein-Bey-Abina, S., Lankester, A. C., Bredius, R. G. M., Driessen, G. J. A., Thrasher, A. J., Baum, C., Cavazzana-Calvo, M., van Dongen, J. J. M., and Staal, F. J. T.

Subjects
*SEVERE combined immunodeficiency, *CYTOKINES, *MUTAGENESIS, *GENETIC transformation, *GENE therapy, *T cell receptors, *BONE marrow transplantation, *B cells, *T cells, *ANIMAL experimentation, *BONE marrow, *CELL physiology, *CELL receptors, *COMPARATIVE studies, *ENZYME-linked immunosorbent assay, *FLOW cytometry, *GENES, *GENETIC techniques, *IMMUNOGLOBULINS, *RESEARCH methodology, *MEDICAL cooperation, *MICE, *POLYMERASE chain reaction, *PROTEINS, *RESEARCH, *RESEARCH funding, *RETROVIRUSES, *RNA, *SPLEEN, *WESTERN immunoblotting, *EVALUATION research, *REVERSE transcriptase polymerase chain reaction, *THERAPEUTICS, *PHYSIOLOGY
Abstract

Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR Vβ gene segment usage was comparable to wild-type (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors. [ABSTRACT FROM AUTHOR]

Published
2011
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127. Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure.

Author

Boelens, J. J., Wynn, R. F., O'Meara, A., Veys, P., Bertrand, Y., Souillet, G., Wraith, J. E., Fischer, A., Cavazzana-Calvo, M., Sykora, K. W., Sedlacek, P., Rovelli, A., Uiterwaal, C. S. P. M., and Wulffraat, N.

Subjects
*HEMATOPOIETIC stem cell transplantation, *LYSOSOMAL storage diseases, *MUCOPOLYSACCHARIDOSIS, *GRAFT rejection, *DISEASE risk factors, *T cells
Abstract

Hurler's syndrome (HS), the most severe form of mucopolysaccharidosis type-I, causes progressive deterioration of the central nervous system and death in childhood. Allogeneic stem cell transplantation (SCT) before the age of 2 years halts disease progression. Graft failure limits the success of SCT. We analyzed data on HS patients transplanted in Europe to identify the risk factors for graft failure. We compared outcomes in 146 HS patients transplanted with various conditioning regimens and grafts. Patients were transplanted between 1994 and 2004 and registered to the European Blood and Marrow Transplantation database. Risk factor analysis was performed using logistic regression. ‘Survival’ and ‘alive and engrafted’-rate after first SCT was 85 and 56%, respectively. In multivariable analysis, T-cell depletion (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04–0.71; P=0.02) and reduced-intensity conditioning (OR 0.08; 95% CI 0.02–0.39; P=0.002) were the risk factors for graft failure. Busulfan targeting protected against graft failure (OR 5.76; 95% CI 1.20–27.54; P=0.028). No difference was noted between cell sources used (bone marrow, peripheral blood stem cells or cord blood (CB)); however, significantly more patients who received CB transplants had full-donor chimerism (OR 9.31; 95% CI 1.06–82.03; P=0.044). These outcomes may impact the safety/efficacy of SCT for ‘inborn-errors of metabolism’ at large. CB increased the likelihood of sustained engraftment associated with normal enzyme levels and could therefore be considered as a preferential cell source in SCT for ‘inborn errors of metabolism’.Bone Marrow Transplantation (2007) 40, 225–233; doi:10.1038/sj.bmt.1705718; published online 28 May 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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129. The VAD chemotherapy regimen plus a G-CSF dose of 10 μg/kg is as effective and less toxic than high-dose cyclophosphamide plus a G-CSF dose of 5 μg/kg for progenitor cell mobilization: results from a monocentric study of 82 patients.

Author

Lefrère, F., Zohar, S., Ghez, D., Delarue, R., Audat, F., Suarez, F., Hermine, O., Damaj, G., Maillard, N., Ribeil, J. A., Azagury, M., Misbahi, R., Jondeau, K., Cavazzana-Calvo, M., Dal Cortivo, L., and Varet, B.

Subjects
*STEM cells, *MULTIPLE myeloma, *B cell lymphoma, *GRANULOCYTE-colony stimulating factor, *COLONY-stimulating factors (Physiology), *LEUKAPHERESIS
Abstract

A study was conducted to compare the efficiency and toxicity of two peripheral blood stem cell (PBSC) mobilization procedures for newly diagnosed patients with multiple myeloma. Patients from group 1 (n=51) were treated by high-dose cyclophosphamide (HD-CY) plus G-CSF (5 μg/kg/day), and the second group (n=31) by VAD regimen plus G-CSF administration (10 μg/kg/day). Successful mobilization, defined by a minimal count of 2.5 × 106 CD34+ cells/kg collected, was achieved in 96 and 90% of patients in groups 1 and 2, respectively (P=0.15). The mean peripheral blood CD34+ cells concentration and the mean CD34+ cells/kg collected were higher in group 2 than in the group 1 (P=0.05). The mean number of leukaphereses necessary to collect a count of 2.5 × 106 CD34+ cells/kg was reduced in group 2 compared to group 1. Adverse events, blood products consumption and time spent in the hospital were significantly greater after HD-CY. In conclusion, VAD plus a G-CSF dose of 10 μg/kg administration seems preferential to HD-CY plus a G-CSF dose of 5 μg/kg for PBSC collection because of equivalent or better efficiency in stem cell mobilization, strong favorable toxicity profile and reduced cost.Bone Marrow Transplantation (2006) 37, 725–729. doi:10.1038/sj.bmt.1705308; published online 6 March 2006 [ABSTRACT FROM AUTHOR]

Published
2006
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130. Improving immune reconstitution while preventing GvHD in allogeneic stem cell transplantation.

Author

André-Schmutz, I., Cortivo, L. Dal, Fischer, A., and Cavazzana-Calvo, M.

Subjects
*TRANSPLANTATION of organs, tissues, etc., *STEM cells, *T cells, *BONE marrow cells, *GENETIC disorders, *VIRUS diseases
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematologic malignancies and inherited disorders of the hematopoietic system. Ex vivo T-cell depletion (TCD) of the graft and post-transplantation immunosuppression efficiently prevents the development of GvHD in no- MHC-identical settings. However, the consequence of these non-specific strategies is a long-lasting immunodeficiency associated with increased incidence of disease relapse, graft rejection and reactivation of viral infections. Donor lymphocyte infusion, which is used for treating leukemic relapse after allogeneic HSCT, can result in severe GvHD. Several strategies are being optimized specifically to inactivate anti-host T cells while preserving anti-leukemic or anti-microbial immunocompetence. Based on the ex vivo or in vivo elimination of anti-host T cells, or on the modulation of their anti-host activity, these approaches, which have been explored extensively in pre-clinical studies and tested in some preliminary clinical trials, are discussed in this paper. [ABSTRACT FROM AUTHOR]

Published
2005
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131. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Author

Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss I, Debré M, Fraitag S, Blanche S, Cavazzana-Calvo M, de Saint Basile G, de Villartay JP, Giliani S, Orth G, Casanova JL, Bodemer C, Fischer A, Laffort, Caroline, Le Deist, Françoise, Favre, Michel, and Caillat-Zucman, Sophie

Abstract

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity. [ABSTRACT FROM AUTHOR]

Published
2004
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132. Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors.

Author

Caillat-Zucman, S., Le Deist, F., Haddad, E., Gannaǵe, M., Cortivo, L. Dal, Jabado, N., Hacein-Bey-Abina, S., Blanche, S., Casanova, J.-L., Fischer, A., and Cavazzana-Calvo, M.

Subjects
*HLA histocompatibility antigens, *HEMATOPOIETIC stem cell transplantation, *BONE marrow cells, *HEMATOPOIETIC system, *BLOOD cells, *STEM cells, *TRANSPLANTATION of organs, tissues, etc.
Abstract

Hematological inherited diseases can be cured by hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling donor (MSD), but the outcome of unrelated donors (URD) or haploidentical donors (HMD) has been a cause of concern. In all, 94 children affected with inherited diseases underwent HSCT at a single center using MSD (group A, n = 31), URD (group B, n = 23) or HMD (group C, n = 40). There was no difference in the rate of engraftment or in the incidence of grades III—IV acute graft-versus-host disease (GVHD) between the groups. Survival rate was 80.6% in group A, 62.5% in group B and 47.5% in group C (P = 0.023). In group B, survival rate was 73.7% in the subgroup with zero or one class I mismatch, and 25% in the subgroup with two or more class I mismatches (P = 0.04). In group C, survival rate was 83.3% in the 9/10-identical subgroup, 64.3% in the seven or 8/10 subgroup, and 25% in the five or 6/10 subgroup (P = 0.0007). Thus, engraftment, incidence of GVHD and survival are similar in recipients of grafts from MSD, URD with 0–1 class I-mismatch, or HMD with at least 7/10 HLA matches. The low success of HSCT using more disparate donors suggests reserving them for patients with very poor prognosis. [ABSTRACT FROM AUTHOR]

Published
2004
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133. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99.

Author

Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A, European Group for Blood and Marrow Transplantation, and European Society for Immunodeficiency

Abstract

Background: Transplantation of allogeneic haemopoietic stem cells can cure several primary immunodeficiencies. This European report focuses on the long-term results of such procedures done between 1968 and December, 1999, for primary immunodeficiencies.Methods: The report includes data from 37 centres in 18 countries, which participated in a European registry for stem-cell transplantation in severe combined immuno deficiencies (SCID) and in other immunodeficiency disorders (non-SCID). 1082 transplants in 919 patients were studied (566 in 475 SCID patients, 512 in 444 non-SCID patients; four procedures excluded owing to insufficient data). Minimum follow-up of 6 months was required.Findings: In SCID, 3-year survival with sustained engraftment was significantly better after HLA-identical than after mismatched transplantation (77% vs 54%; p=0.002) and survival improved over time. In HLA-mismatched stem-cell transplantation, B(-) SCID had poorer prognosis than B(+) SCID. However, improvement with time occurred in both SCID phenotypes. In non-SCID, 3-year survival after genotypically HLA-matched, phenotypically HLA-matched, HLA-mismatched related, and unrelated-donor transplantation was 71%, 42%, 42%, and 59%, respectively (p=0.0006). Acute graft versus host disease predicted poor prognosis whatever the donor origin except in related HLA-identical transplantation in SCID.Interpretation: The improvement in survival over time indicates more effective prevention and treatment of disease-related and procedure-related complications--eg, infections and graft versus host disease. An important factor is better prevention of graft versus host disease in the HLA-non-identical setting by use of more efficient methods of T-cell depletion. For non-SCID, stem-cell transplantation can provide a cure, and grafts from unrelated donors are almost as beneficial as those from genetically HLA-identical relatives. [ABSTRACT FROM AUTHOR]

Published
2003
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137. Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

Author

Juan A. Bueren, Susana Navarro, Jennifer E. Adair, Paula Río, Michael Antoniou, Cynthia C. Bartholomae, Julián Sevilla, Pamela S. Becker, Anne Galy, Adrian J. Thrasher, Bruce R. Blazar, David A. Williams, Marina Cavazzana-Calvo, Thomas Carroll, Luigi Naldini, Robert Dalgleish, Els Verhoeyen, Helmut Hanenberg, Raffaele Renella, H. Bobby Gaspar, D. Wade Clapp, Dirk Lindeman, Hans-Peter Kiem, Jakub Tolar, John E. Wagner, Manfred Schmidt, Christof von Kalle, Tolar, J, Adair, Je, Antoniou, M, Bartholomae, Cc, Becker, P, Blazar, Br, Bueren, J, Carroll, T, Cavazzana Calvo, M, Clapp, Dw, Dalgleish, R, Galy, A, Gaspar, Hb, Hanenberg, H, Von Kalle, C, Kiem, Hp, Lindeman, D, Naldini, Luigi, Navarro, S, Renella, R, Rio, P, Sevilla, J, Schmidt, M, Verhoeyen, E, Wagner, Je, Williams, Da, Thrasher, Aj, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Immunologie des maladies infectieuses allergiques et autoimmunes, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, medicine.medical_specialty, Stem Cell Transplantation/methods, Genetic enhancement, [SDV]Life Sciences [q-bio], Review, Genetic Therapy/*methods, Gene product, 03 medical and health sciences, 0302 clinical medicine, Fanconi anemia, Internal medicine, Drug Discovery, medicine, Genetics, Humans, Gene, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, Hematopoietic Stem Cells/cytology, Fanconi Anemia/*therapy, business.industry, Genetic Therapy, Congresses as Topic, medicine.disease, Hematopoietic Stem Cells, 3. Good health, Clinical trial, Transplantation, Fanconi Anemia, 030220 oncology & carcinogenesis, Immunology, Savior sibling, Molecular Medicine, Stem cell, business, Stem Cell Transplantation
Abstract

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.

Published
2011
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138. Gene therapy for primary immunodeficiencies: Part 2

Author

Reinhard Seger, Alessandro Aiuti, Rosa Bacchetta, Anna Villa, Marina Cavazzana-Calvo, Aiuti, Alessandro, Bacchetta, R, Seger, R, Villa, A, Cavazzana Calvo, M., and University of Zurich

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Wiskott–Aldrich syndrome, Genetic enhancement, Immunology, Genetic Vectors, 610 Medicine & health, Granulomatous Disease, Chronic, Bioinformatics, Exfoliation Syndrome, Insertional mutagenesis, 03 medical and health sciences, 0302 clinical medicine, Chronic granulomatous disease, Animals, Wiskott-Aldrich Syndrome, Gene Transfer Techniques, Severe Combined Immunodeficiency, Humans, Clinical Trials as Topic, Genetic Therapy, Forecasting, Immunologic Deficiency Syndromes, hemic and lymphatic diseases, medicine, Immunology and Allergy, Chronic, 030304 developmental biology, Therapeutic strategy, Settore MED/38 - Pediatria Generale e Specialistica, 2403 Immunology, 0303 health sciences, Severe combined immunodeficiency, business.industry, IPEX syndrome, medicine.disease, 3. Good health, Clinical trial, 10036 Medical Clinic, 030220 oncology & carcinogenesis, 2723 Immunology and Allergy, Granulomatous Disease, business
Abstract

Gene therapy has become an attractive alternative therapeutic strategy to allogeneic transplant for primary immunodeficiencies (PIDs) owing to known genetic defects. Clinical trials using gammaretroviral vectors have demonstrated the proof of principle of gene therapy for Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD), but have also highlighted limitations of the technology. New strategies based on vectors that can achieve more robust correction with less risk of insertional mutagenesis are being developed. In this review we present the status of gene therapy for WAS and CGD, and discuss the emerging application of similar strategies to a broader range of PIDs, such as IPEX syndrome.

Published
2012

139. Gene therapy for primary immunodeficiencies: Part 1

Author

Marina Cavazzana-Calvo, Alessandro Aiuti, Alain Fischer, Salima Hacein-Bey-Abina, Cavazzana Calvo, M, Fischer, A, Hacein Bey Abina, S, and Aiuti, Alessandro

Subjects
Allogeneic transplantation, Adenosine Deaminase, Genetic enhancement, Immunology, Animals, Humans, Hematopoietic Stem Cell Transplantation, Clinical Trials as Topic, X-Linked Combined Immunodeficiency Diseases, Disease Models, Animal, Genetic Therapy, Immunologic Deficiency Syndromes, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Adenosine deaminase, Genome editing, medicine, Immunology and Allergy, 030304 developmental biology, Settore MED/38 - Pediatria Generale e Specialistica, 0303 health sciences, biology, business.industry, Animal, Hematopoietic stem cell, Gene targeting, medicine.disease, 3. Good health, Adenosine deaminase deficiency, Clinical trial, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Models, biology.protein, business
Abstract

Over 60 patients affected by SCID due to IL2RG deficiency (SCID-X1) or adenosine deaminase (ADA)-SCID have received hematopoietic stem cell gene therapy in the past 15 years using gammaretroviral vectors, resulting in immune reconstitution and clinical benefit in the majority of them. However, the occurrence of insertional oncogenesis in the SCID-X1 trials has led to the development of new clinical trials based on integrating vectors with improved safety design as well as investigation on new technologies for highly efficient gene targeting and site-specific gene editing. Here we will present the experience and perspectives of gene therapy for SCID-X1 and ADA-SCID and discuss the pros and cons of gene therapy in comparison to allogeneic transplantation.

Published
2012

140. Insertion Sites in Engrafted Cells Cluster Within a Limited Repertoire of Genomic Areas After Gammaretroviral Vector Gene Therapy

Author

Adrian J. Thrasher, Fulvio Mavilio, Anna Paruzynski, Steven J. Howe, Claudia Cattoglio, Manuel Grez, Hanno Glimm, Dieter Hoelzer, H. Bobby Gaspar, Gerard Wagemaker, Manfred Schmidt, Annette Deichmann, Ulrich Abel, Richard Gabriel, Alessandro Aiuti, Marina Cavazzana-Calvo, Kerstin Schwarzwaelder, Salima Hacein-Bey-Abina, Monique M A Verstegen, Cynthia C. Bartholomae, Cynthia E. Dunbar, Barbara Cassani, Alain Fischer, Christof von Kalle, Marion Ott, Reinhard Seger, Martijn H. Brugman, Anne Arens, Christopher Baum, Deichmann, A, Brugman, Mh, Bartholomae, Cc, Schwarzwaelder, K, Verstegen, Mm, Howe, Sj, Arens, A, Ott, Mg, Hoelzer, D, Seger, R, Grez, M, Hacein Bey Abina, S, Cavazzana Calvo, M, Fischer, A, Paruzynski, A, Gabriel, R, Glimm, H, Abel, U, Cattoglio, C, Mavilio, F, Cassani, B, Aiuti, Alessandro, Dunbar, Ce, Baum, C, Gaspar, Hb, Thrasher, Aj, von Kalle, C, Schmidt, M, Wagemaker, G., Hematology, and Pediatrics

Subjects
Primates, Animals, Chromosome Mapping, Gammaretrovirus, Gene Regulatory Networks, Genetic Therapy, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Humans, Mice, Transplants, X-Linked Combined Immunodeficiency Diseases, Genome, Virus Integration, Molecular Biology, Molecular Medicine, Genetics, Drug Discovery3003 Pharmaceutical Science, Pharmacology, Genetic enhancement, Gene regulatory network, 03 medical and health sciences, 0302 clinical medicine, Retrovirus, In vivo, Drug Discovery, medicine, Progenitor cell, Gene, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, biology, biology.organism_classification, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Original Article
Abstract

Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions.

Published
2011

141. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease

Author

Claire, Booth, Kimberly C, Gilmour, Paul, Veys, Andrew R, Gennery, Mary A, Slatter, Helen, Chapel, Paul T, Heath, Colin G, Steward, Owen, Smith, Anna, O'Meara, Hilary, Kerrigan, Nizar, Mahlaoui, Marina, Cavazzana-Calvo, Alain, Fischer, Despina, Moshous, Stephane, Blanche, Jana, Pachlopnik Schmid, Jana, Pachlopnick-Schmid, Sylvain, Latour, Genevieve, de Saint-Basile, Michael, Albert, Gundula, Notheis, Nikolaus, Rieber, Brigitte, Strahm, Henrike, Ritterbusch, Arjan, Lankester, Nico G, Hartwig, Isabelle, Meyts, Alessandro, Plebani, Annarosa, Soresina, Andrea, Finocchi, Claudio, Pignata, Emilia, Cirillo, Sonia, Bonanomi, Christina, Peters, Krzysztof, Kalwak, Srdjan, Pasic, Petr, Sedlacek, Janez, Jazbec, Hirokazu, Kanegane, Kim E, Nichols, I Celine, Hanson, Neena, Kapoor, Elie, Haddad, Morton, Cowan, Sharon, Choo, Joanne, Smart, Peter D, Arkwright, Hubert B, Gaspar, Pediatrics, Booth, C., Gilmour, K. C., Veys, P., Gennery, A. R., Slatter, M. A., Chapel, H., Heath, P. T., Steward, C. G., Smith, O., O'Meara, A., Kerrigan, H., Mahlaoui, N., Cavazzana Calvo, M., Fischer, A., Moshous, D., Blanche, S., Pachlopnik Schmid, J., Latour, S., de Saint Basile, G., Albert, M., Notheis, G., Rieber, N., Strahm, B., Ritterbusch, H., Lankester, A., Hartwig, N. G., Meyts, I., Plebani, A., Soresina, A., Finocchi, A., Pignata, Claudio, Cirillo, E., Bonanomi, S., Peters, C., Kalwak, K., Pasic, S., Sedlacek, P., Jazbec, J., Kanegane, H., Nichols, K. E., Hanson, I. C., Kapoor, N., Haddad, E., Cowan, M., Choo, S., Smart, J., Arkwright, P. D., and Gaspar, H. B.

Subjects
Male, Pediatrics, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Clinical Trials and Observations, medicine.medical_treatment, Hematopoietic stem cell transplantation, medicine.disease_cause, Biochemistry, 0302 clinical medicine, Signaling Lymphocytic Activation Molecule Family Member 1, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, X-Linked Lymphoproliferative Syndrome, Signaling Lymphocytic Activation Molecule Associated Protein, Child, Immunodeficiency, 0303 health sciences, Hematopoietic Stem Cell Transplantation, Intracellular Signaling Peptides and Proteins, Hematology, Middle Aged, 3. Good health, Survival Rate, Child, Preschool, Female, SAP, Adult, medicine.medical_specialty, Adolescent, Immunology, Lymphoproliferative disorders, Receptors, Cell Surface, XLP, SAP, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, Young Adult, Antigens, CD, XLP, Humans, Survival rate, 030304 developmental biology, Settore MED/38 - Pediatria Generale e Specialistica, Hemophagocytic lymphohistiocytosis, business.industry, Infant, Newborn, X-linked lymphoproliferative disease, Infant, Cell Biology, Immune dysregulation, medicine.disease, stem-cell transplantation barr-virus infection hemophagocytic lymphohistiocytosis cutting edge t-cells lymphocytic vasculitis encoding gene sap activation mononucleosis, Lymphoproliferative Disorders, Mutation, business, 030215 immunology
Abstract

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Published
2011

142. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

Author

Floriane Fusil, Stany Chrétien, Riccardo Sgarra, Beatrix Gillet-Legrand, Françoise Bernaudin, Nabil Kabbara, Robert Girot, Philippe Leboulch, Laure Caccavelli, Maria Denaro, Frédéric Galactéros, Julian D. Down, Marina Cavazzana-Calvo, Emmanuel Payen, Kathleen M. Hehir, Leila Maouche-Chretien, Bernard Gourmel, Kenneth Cornetta, Frederick D. Bushman, Axel Polack, Alain Fischer, Patrick Aubourg, Salima Hacein-Bey-Abina, Gérard Socié, Jérôme Larghero, Karen A. Westerman, Gary P. Wang, Nathalie Cartier, Eliane Gluckman, Yves Beuzard, Arthur Bank, Ronald Dorazio, Troy Brady, Geert Jan Mulder, Resy Cavallesco, Olivier Negre, Bruno Dalle, Jean Soulier, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Genetix-France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Microbiology, University of Pennsylvania [Philadelphia], Genetix Pharmaceuticals, Genetics Division, Boston, Brigham and Women's Hospital [Boston], Department of Life Sciences, Trieste, University of Trieste, Service d'hématologie pédiatrique, Hôpital intercommunal de Créteil, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medicine and Department of Genetics and Development, Columbia University [New York], Departments of Hematology, Université Paris Diderot - Paris 7 (UPD7), Institute of Hematology, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical and Molecular Genetics, Indiana University [Bloomington], Indiana University System-Indiana University System, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Università degli studi di Trieste = University of Trieste, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Maladies Emergentes et des Thérapies Innovantes ( IMETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Thérapie génique et contrôle de l'expansion cellulaire ( UMR E007 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Cambridge, MA, Department of Biology, Paris, Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Cavazzana Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet Legrand, B., Caccavelli, L., Sgarra, Riccardo, Maouche Chrétien, L., Bernaudin, F., Girot, R., Dorazio, R., Mulder, G. J., Polack, A., Bank, A., Soulier, J., Larghero, J., Kabbara, N., Dalle, B., Gourmel, B., Socie, G., Chrétien, S., Cartier, N., Aubourg, P., Fischer, A., Cornetta, K., Galacteros, F., Beuzard, Y., Gluckman, E., Bushman, F., Hacein Bey Abina, S., and Leboulch, P.

Subjects
Male, Transcriptional Activation, Time Factors, Adolescent, Genetic enhancement, Genetic Vectors, Gene Expression, Bone Marrow Cells, beta-Globins, Gene Terapy HMGA2, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Southeast asian, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Homeostasis, Humans, Blood Transfusion, RNA, Messenger, Progenitor cell, 030304 developmental biology, 0303 health sciences, Blood Cells, Multidisciplinary, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, HMGA2 Protein, Lentivirus, beta-Thalassemia, Genetic transfer, Beta thalassemia, Genetic Therapy, medicine.disease, Clone Cells, 3. Good health, Transplantation, MicroRNAs, Haematopoiesis, Organ Specificity, Child, Preschool, 030220 oncology & carcinogenesis, Immunology, Stem cell
Abstract

Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives. So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event. More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months. The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage. Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide. For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells. Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia. The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.

Published
2010
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143. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome

Author

Anna Casati, Marita Bosticardo, Fabio Facchetti, Marina Cavazzana-Calvo, Paolo Vezzoni, Veronica Marrella, Manuela Battaglia, Pietro Luigi Poliani, Brigitte Lemercier, Maria Grazia Roncarolo, Marie-Lise Gougeon, Fabio Grassi, Luigi D. Notarangelo, Francesca Rucci, Maria Ravanini, Anna Villa, Laura Frascoli, Marrella, V, Poliani, Pl, Casati, A, Rucci, F, Frascoli, L, Gougeon, Ml, Lemercier, B, Bosticardo, M, Ravanini, M, Battaglia, MARCO MARIA, Roncarolo, MARIA GRAZIA, Cavazzana Calvo, M, Facchetti, F, Notarangelo, Ld, Vezzoni, P, Grassi, F, and Villa, A.

Subjects
Omenn sydnrome, Glutamine, Transgene, mouse model, B cell defect, Mutagenesis (molecular biology technique), Mice, Transgenic, Biology, Arginine, medicine.disease_cause, Omenn Syndrome, Immune tolerance, Mice, RAG2, Immune Tolerance, medicine, Animals, Humans, Eosinophilia, rag genes, Cells, Cultured, T cell defect, Mutation, autoimmunity, T-cell receptor, Genetic Diseases, Inborn, Immunologic Deficiency Syndromes, General Medicine, medicine.disease, Mice, Mutant Strains, Omenn syndrome, DNA-Binding Proteins, Mice, Inbred C57BL, Disease Models, Animal, Amino Acid Substitution, Immunology, Mutagenesis, Site-Directed, Commentary, medicine.symptom, Research Article
Abstract

Rag enzymes are the main players in V(D)J recombination, the process responsible for rearrangement of TCR and Ig genes. Hypomorphic Rag mutations in humans, which maintain partial V(D)J activity, cause a peculiar SCID associated with autoimmune-like manifestations, Omenn syndrome (OS). Although a deficient ability to sustain thymopoiesis and to produce a diverse T and B cell repertoire explains the increased susceptibility to severe infections, the molecular and cellular mechanisms underlying the spectrum of clinical and immunological features of OS remain poorly defined. In order to better define the molecular and cellular pathophysiology of OS, we generated a knockin murine model carrying the Rag2 R229Q mutation previously described in several patients with OS and leaky forms of SCID. These Rag2(R229Q/R229Q) mice showed oligoclonal T cells, absence of circulating B cells, and peripheral eosinophilia. In addition, activated T cells infiltrated gut and skin, causing diarrhea, alopecia, and, in some cases, severe erythrodermia. These findings were associated with reduced thymic expression of Aire and markedly reduced numbers of naturally occurring Tregs and NKT lymphocytes. In conclusion, Rag2(R229Q/R229Q) mice mimicked most symptoms of human OS; our findings support the notion that impaired immune tolerance and defective immune regulation are involved in the pathophysiology of OS.

Published
2007
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148. Gene therapy of primary T cell immunodeficiencies.

Author

Fischer A, Hacein-Bey-Abina S, and Cavazzana-Calvo M

Subjects
Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Clinical Trials as Topic, Genetic Vectors adverse effects, Humans, Lentivirus genetics, Retroviridae genetics, Severe Combined Immunodeficiency genetics, Treatment Outcome, Genetic Therapy methods, Severe Combined Immunodeficiency therapy, T-Lymphocytes immunology, Wiskott-Aldrich Syndrome therapy
Abstract

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Published
2013
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149. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.

Author

Boelens JJ, Aldenhoven M, Purtill D, Ruggeri A, Defor T, Wynn R, Wraith E, Cavazzana-Calvo M, Rovelli A, Fischer A, Tolar J, Prasad VK, Escolar M, Gluckman E, O'Meara A, Orchard PJ, Veys P, Eapen M, Kurtzberg J, and Rocha V

Subjects
Adolescent, Child, Child, Preschool, Female, Hematopoietic Stem Cell Transplantation adverse effects, Histocompatibility Testing, Humans, Infant, Male, Mucopolysaccharidosis I epidemiology, Mucopolysaccharidosis I mortality, Myeloablative Agonists adverse effects, Retrospective Studies, Tissue Donors, Tissue and Organ Procurement methods, Transplantation Conditioning adverse effects, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells cytology, Mucopolysaccharidosis I therapy, Myeloablative Agonists therapeutic use, Transplantation Conditioning methods
Abstract

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

Published
2013
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150. [Gene therapy: where do we stand?].

Author

Cavazzana-Calvo M

Subjects
Genetic Vectors, Humans, Genetic Therapy methods, Genetic Therapy trends
Abstract

Gene therapy is a form of molecular medicine based on the addition of a corrected copy of a gene to the somatic cells of an individual in order to cure or to alleviate the underlying disease. This approach provides new targeted therapies for an increasing number of acquired or inherited diseases. Since its very first beginning in the 90's essentially for cancer treatment, this therapeutical approach has met unpredicted obstacles as well as true success. Recently, significant clinical benefits have been reported for several inherited diseases of the hematopoietic system but also of the retina and some cancers, widening its application provided that severe adverse events can be efficiently and stably prevented.

Published
2013

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