Gene Therapy for Primary Immunodeficiencies

Thrasher, Adrian J.

doi:10.1016/j.iac.2008.02.001

Cited by 12 publications

(6 citation statements)

References 86 publications

(15 reference statements)

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“…Procedures to restore immunity include either allogeneic hematopoietic stem-cell transplantation or autologous gene therapy. [4][5][6][7][8] Hematopoietic stemcell transplants from a matched sibling donor are effective but available for less than 20% of patients, and transplants from alternative donors are associated with an increased risk of graft-versus-host disease and incomplete immune reconstitution. [9][10][11][12][13][14] Gene therapy is an experimental treatment that inserts a normal copy of the coding region of IL2RG into the genome of a patient's own hematopoietic stem cells.…”

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confidence: 99%

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

et al. 2019

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BACKGROUND Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four in-fants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, .)

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confidence: 99%

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

et al. 2019

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“… 14 Although HIV infection and LVV transduction utilize different mechanisms to overcome the cellular membrane barrier, it has been shown that other methods used to increase transduction efficiency of LVV in HSPCs, such as spinoculation, which has been utilized to transduce HSPCs with both gammaretroviral vector and LVV, cause a similar activation of cortical actin dynamics, suggesting that this cellular membrane entry barrier might be a common restriction point for both HIV infection and LVV transduction. 15 , 16 , 17 , 18 …”

Section: Introductionmentioning

confidence: 99%

Staurosporine Increases Lentiviral Vector Transduction Efficiency of Human Hematopoietic Stem and Progenitor Cells

Lewis

Christiansen

McKenzie

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Lentiviral vector (LVV)-mediated transduction of human CD34+ hematopoietic stem and progenitor cells (HSPCs) holds tremendous promise for the treatment of monogenic hematological diseases. This approach requires the generation of a sufficient proportion of gene-modified cells. We identified staurosporine, a serine/threonine kinase inhibitor, as a small molecule that could be added to the transduction process to increase the proportion of genetically modified HSPCs by overcoming a LVV entry barrier. Staurosporine increased vector copy number (VCN) approximately 2-fold when added to mobilized peripheral blood (mPB) CD34+ cells prior to transduction. Limited staurosporine treatment did not affect viability of cells post-transduction, and there was no difference in in vitro colony formation compared to vehicle-treated cells. Xenotransplantation studies identified a statistically significant increase in VCN in engrafted human cells in mouse bone marrow at 4 months post-transplantation compared to vehicle-treated cells. Prostaglandin E2 (PGE2) is known to increase transduction efficiency of HSPCs through a different mechanism. Combining staurosporine and PGE2 resulted in further enhancement of transduction efficiency, particularly in short-term HSPCs. The combinatorial use of small molecules, such as staurosporine and PGE2, to enhance LVV transduction of human CD34+ cells is a promising method to improve transduction efficiency and subsequent potential therapeutic benefit of gene therapy drug products.

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“…Gene therapy to counter hematopoietic diseases has met with great success in recent years. Patients suffering from X-linked severe combined immunodeficiency, adenosin-deaminase deficiency, X-linked chronic granulomatous disease and Wiskott-Aldrich syndrome have benefited from the reconstitution of their immune systems by gene therapy (reviewed in the study by Thrasher 1 and Aiuti et al 2 ). Nevertheless, some patients have experienced undesired side effects in the form of lymphoproliferation because of integration of the transgene in the vicinity of transcriptionally active areas.…”

Section: Introductionmentioning

confidence: 99%

A tissue-specific, activation-inducible, lentiviral vector regulated by human CD40L proximal promoter sequences

et al. 2010

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The application of new protocols for gene therapy against monogenic diseases requires the development of safer therapeutic vectors, particularly in the case of diseases in which expression of the mutated gene is subject to fine regulation, as it is with CD40L (CD154). CD40L, the gene mutated in the X-linked hyper-immunoglobulin M syndrome (HIGM1), is tightly regulated to allow surface expression of its product only on T cells stimulated by antigen encounter. Previous studies in an HIGM1 animal model showed that transduction of progenitor cells corrected the syndrome but caused a thymic lymphoproliferative disease because of the unregulated expression of the transgene by constitutive vectors. To develop a tissue-specific, activation-inducible, lentiviral vector (LV) for gene therapy to counter HIGM1, we have constructed two self-inactivating LVs, pCD40L-eGFP and pCD40L-CD40L, regulated by a 1.3 kb fragment of the human CD40L proximal promoter. The expression of pCD40L-eGFP LV is restricted to cells in which mRNA transcripts of the endogenous CD40L gene can be detected. Moreover, the expression of the reporter gene in primary T lymphocytes depends on the activation state of the cells. Remarkably, primary HIGM1 lymphocytes transduced with pCD40L-CD40L LV expressed CD40L only after T-cell stimulation. Therefore, the CD40L-promoter-driven vectors are able to achieve a near-physiological expression pattern that follows very closely that of the endogenous CD40L gene.

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Gene Therapy for Primary Immunodeficiencies

Cited by 12 publications

References 86 publications

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

Staurosporine Increases Lentiviral Vector Transduction Efficiency of Human Hematopoietic Stem and Progenitor Cells

A tissue-specific, activation-inducible, lentiviral vector regulated by human CD40L proximal promoter sequences

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