Author
Hacein-Bey S
Bio: Hacein-Bey S is an academic researcher from University of Paris. The author has contributed to research in topics: Severe combined immunodeficiency & Genetic enhancement. The author has an hindex of 5, co-authored 10 publications receiving 2628 citations.
Papers
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TL;DR: A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.
Abstract: Severe combined immunodeficiency-X1 (SCID-X1) is an X-linked inherited disorder characterized by an early block in T and natural killer (NK) lymphocyte differentiation. This block is caused by mutations of the gene encoding the gammac cytokine receptor subunit of interleukin-2, -4, -7, -9, and -15 receptors, which participates in the delivery of growth, survival, and differentiation signals to early lymphoid progenitors. After preclinical studies, a gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells. After a 10-month follow-up period, gammac transgene-expressing T and NK cells were detected in two patients. T, B, and NK cell counts and function, including antigen-specific responses, were comparable to those of age-matched controls. Thus, gene therapy was able to provide full correction of disease phenotype and, hence, clinical benefit.
2,639 citations
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01 Nov 2002TL;DR: In an attempt to assess the ability of an allodepleted T-cell “add-back” to exert an anti-viral infection effect, immunity to EBV and CMV infections was tested at 1 month after infusion in two infected patients, included the one presenting with cerebral and pulmonary lesions.
Abstract: ALLOGENEIC stem cell transplantation is the treatment of choice for many hematologic malignancies or inherited disorders. In the partially incompatible HLA setting ex vivo T-cell depletion of the graft and posttransplantation immunosuppression prevent development of graft-versus-host disease (GVHD), but lead in turn to a delay in immune reconstitution and a concordant increase in the incidence of opportunistic infections and disease relapses. To deplete the T cells responsible for GVHD but retain T cells responsible for the anti-leukemic and antiinfectious activities, we have developed an in vitro procedure to allo-activate donor T cells responsible for GVHD and eliminate them with an immunotoxin that is reactive with the cell surface activation antigen CD25. We infused the remaining allodepleted T cells between day 15 and 47 into pediatric patients with acquired or congenital hematopoietic disorders who received hematopoietic stem cell transplants (HSCT) on day 0. We evaluated the rates of GVHD and opportunistic infections as well as the time to immune reconstitution. Sixteen infusions of allodepleted T cells, ranging from 1 to 8 10 cells/kg were administered to pediatric patients between March 1999 and April 2001, none of whom received prophylactic therapy for GVHD. Despite the risk of transfusing donor T cells activated against recipient alloantigens ex vivo, GVHD greater than grade II was not observed. Two patients (13%) developed grade 1 aGVHD limited to skin, and two others (13%) developed grade II aGVHD with one case involving both the skin and gastrointestinal tract. All cases resolved with treatment. Interestingly, all cases correlated with a residual alloproliferation of 1% (P .001) (data not shown). Three patients displayed an active cytomegalovirus (CMV) infection at the time of HSCT that required antiCMV treatment. In addition, one patient (#5) experienced pulmonary and cerebral EBV-induced lymphoproliferation and a varicella zoster virus infection. After the infusion of allodepleted T cells, two types of situations were observed. Patients who did not show major infectious complications or GVHD displayed a progressive increase in the CD4 T-cell compartment, particularly of naive CD45RA phenotype cells, which were detectable by week 14. In contrast, patients who were infected at time of T-cell infusion demonstrated a rapid expansion in the CD4 T-cell compartment with clinically significant numbers of cells, all expressing CD45RO by week 8. In an attempt to assess the ability of an allodepleted T-cell “add-back” to exert an anti-viral infection effect, immunity to EBV and CMV infections was tested at 1 month after infusion in two infected patients, included the one presenting with cerebral and pulmonary lesions. In these two cases, circulating T cells were highly responsive to CMV and EBV as shown by their capacity to secrete -interferon in the presence of an autologous EBV cell line (transfected or not with CMV pp65 antigen) and their capacity to kill CMV pp65-expressing target cells without in vitro restimulation. As shown by CT scan, pulmonary and central nervous system lesions in patient 5 caused by the EBV infection disappeared 11 weeks after the T-cell infusion. For the other patient, CMV antigen was negative 15 weeks post-HSCT (10 weeks postinfusion). Infused allodepleted T cells seem to not recirculate in noninfected patients, an observation that may depend upon the low numbers of infused cells. As illustrated by the three cases of relapse among the five leukemic patients included in the clinical trial, cellular therapy for viral infections is achieved with doses of lymphocytes within the range of the
20 citations
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19 citations
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7 citations
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TL;DR: The most recent advances in gene therapy of different SCIDs are reviewed, with particular regard to ADA-deficient SCID (ADK SCID), the prototype of immunodeficiencies amenable to gene therapy.
Abstract: Severe combined immunodeficiency diseases (SCIDs) are a group of primary im munodeficiencies characterized by profoundly impaired cell-mediated and humoral responses [1,2]. Affected children typically fail to thrive and become ill with recur rent infections caused by bacteria, viruses, and opportunistic pathogens. The mole cular defects have now been identified for the majority of SCID phenotypes and are summarized in Table 1-1 [3-27]. The defects affect lymphocyte receptors [28], sig nal transduction molecules [29], transcription factors [30], and enzymes of purine metabolism such as adenosine deaminase (ADA) [31] and purine nucleoside phos phorilase (PNP) [32]. The identification, cloning, and expression of the genes re sponsible for the different forms of SCID renders them potentially curable with so matic cell gene therapy. The ideal approach to gene therapy would require efficient gene transfer into the stem cell of the hematopoietic system, thus allowing the ap propriate expression of the normal gene into the affected cells of hematopoietic or lymphoid lineage [33-35]. However, initial difficulties in obtaining efficient trans duction of stem cells have led several investigators to approach gene transfer direct ly into differentiated lymphocytes [36-38]. Gene transfer into cells of the lympho hematopoietic system for SCID is currently based on the use of retroviral vectors [33]. ADA-deficiency was the first genetic disorder to be treated with retroviral-me diated gene transfer and, to date, the only SCID treated. Here, we will review the most recent advances in gene therapy of different SCIDs, with particular regard to ADA-deficient SCID (ADK SCID), the prototype of immunodeficiencies amenable to gene therapy.
5 citations
Cited by
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French Institute of Health and Medical Research1, University of Freiburg2, Hospital Research Foundation3, Medical Research Council4, Utrecht University5, Harvard University6, Pasteur Institute7, Babraham Institute8, University of Paris9, Curie Institute10, National Institutes of Health11, University of Sydney12, Ludwig Maximilian University of Munich13, LSU Health Sciences Center New Orleans14
TL;DR: Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
Abstract: We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
3,514 citations
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TL;DR: With the development of a leukaemia-like syndrome in two patients cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.
Abstract: Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.
2,451 citations
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TL;DR: With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-Delivery systems will become an important tool for human gene therapy.
Abstract: The lack of safe and efficient gene-delivery methods is a limiting obstacle to human gene therapy. Synthetic gene-delivery agents, although safer than recombinant viruses, generally do not possess the required efficacy. In recent years, a variety of effective polymers have been designed specifically for gene delivery, and much has been learned about their structure–function relationships. With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-delivery systems will become an important tool for human gene therapy.
2,361 citations
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TL;DR: Two nonviral gene delivery systems using either biodegradable poly(D,Llactide-co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells.
Abstract: The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,Llactide-co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (~200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less
2,189 citations
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TL;DR: Advances in nanoparticle design that overcome heterogeneous barriers to delivery are discussed, arguing that intelligent nanoparticles design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.
Abstract: In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.
2,179 citations