Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

Soheili, Tayebeh; Rivière, Julie; Ricciardelli, Ida; Durand, Alexandra; Verhoeyen, Els; Derrien, Anne‐Céline; Lagresle-Peyrou, Chantal; Basile, Geneviève de Saint; Cosset, François‐Loïc; Amrolia, Persis; André-Schmutz, Isabelle; Cavazzana, Marina

doi:10.1182/blood-2016-07-729871

Cited by 24 publications

(32 citation statements)

References 21 publications

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“…As described previously, 4 we designed a self-inactivating LV carrying a codon-optimized human UNC13D or GFP cDNA under the control of a short elongation factor 1-a (EF1-a) promoter. In a series of independent experiments, Sca1…”

Section: Resultsmentioning

confidence: 99%

“…4 If approved by regulatory bodies, the use of gene-corrected autologous T cells would be a treatment option for FHL3 patients. However, it has recently been demonstrated that (1) NK cell cytotoxicity has a distinct immunoregulatory role in HLH disease, 19 and (2) Munc13-4 has a critical function in platelets and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that, by using a new lentiviral pseudotype (such as the H/F-envelope), high levels of T-cell transduction can be achieved. 4 However, more preclinical studies are needed to further support the use of these new LVs in future clinical trials. In this context, the genetic correction of autologous hematopoietic stem cells (HSCs), which has provided convincing evidence of successful treatment of hematopoietic disorders, 7,8 could be proposed for FHL3 patients.…”

Section: Introductionmentioning

confidence: 99%

“…4 Based on the outcomes of HSCT in FHL patients, T-cell chimerism of at least 10% to 15% is required for efficient remission of HLH. 5,6 Hence, the T cells' transduction efficiency is a key parameter in this strategy.…”

Section: Introductionmentioning

confidence: 99%

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Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

et al. 2017

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“…Recently published preclinical data suggest that lentiviral vector-based T cell gene therapy might be applicable to other inherited and acquired T lymphocyte diseases, such as familial hemophagocytic lymphohistiocytosis types 2 8 and 3 9 immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, 10 and HIV infection 11 . A prerequisite for the efficient achievement of this goal in the clinic is a better understanding of the in vivo cell biology of gene-modified T cells.…”

Section: Introductionmentioning

confidence: 99%

A Nontoxic Transduction Enhancer Enables Highly Efficient Lentiviral Transduction of Primary Murine T Cells and Hematopoietic Stem Cells

Delville

Soheili

Bellier

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Lentiviral vectors have emerged as an efficient, safe therapeutic tool for gene therapy based on hematopoietic stem cells (HSCs) or T cells. However, the monitoring of transduced cells in preclinical models remains challenging because of the inefficient transduction of murine primary T cells with lentiviral vectors, in contrast to gammaretroviral vectors. The use of this later in preclinical proof of concept is not considered as relevant when a lentiviral vector will be used in a clinical trial. Hence, there is an urgent need to develop an efficient transduction protocol for murine cells with lentiviral vectors. Here, we describe an optimized protocol in which a nontoxic transduction enhancer (Lentiboost) enables the efficient transduction of primary murine T cells with lentiviral vectors. The optimized protocol combines low toxicity and high transduction efficiency. We achieved a high-level transduction of murine CD4+ and CD8+ T cells with a VSV-G-pseudotyped lentiviral vector with no changes in the phenotypes of transduced T cells, which were stable and long-lived in culture. This enhancer also increased the transduction of murine HSCs. Hence, use of this new transduction enhancer overcomes the limitations of lentiviral vectors in preclinical experiments and should facilitate the translation of strategies based on lentiviral vectors from the bench to the clinic.

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Advances in basic and clinical immunology in 2016

Chinen

Badran

Geha

et al. 2017

Journal of Allergy and Clinical Immunology

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Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain-containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1). Trials of hematopoietic stem cell transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous virus-specific cytotoxic T cells has proved effective as well. New medications are being explored, such as pioglitazone, which is under study for its role in enhancing the oxidative burst in patients with chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate.

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Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

Cited by 24 publications

References 21 publications

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

A Nontoxic Transduction Enhancer Enables Highly Efficient Lentiviral Transduction of Primary Murine T Cells and Hematopoietic Stem Cells

Advances in basic and clinical immunology in 2016

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