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      Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives

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          Abstract

          Gene therapy protocols require robust and long-term gene expression. For two decades, retrovirus family vectors have offered several attractive properties as stable gene-delivery vehicles. These vectors represent a technology with widespread use in basic biology and translational studies that require persistent gene expression for treatment of several monogenic diseases. Immunogenicity and insertional mutagenesis represent the main obstacles to a wider clinical use of these vectors. Efficient and safe non-viral vectors are emerging as a promising alternative and facilitate clinical gene therapy studies. Here, we present an updated review for beginners and expert readers on retro and lentiviruses and the latest generation of transposon vectors (sleeping beauty and piggyBac) used in stable gene transfer and gene therapy clinical trials. We discuss the potential advantages and disadvantages of these systems such as cellular responses (immunogenicity or genome modification of the target cell) following exogenous DNA integration. Additionally, we discuss potential implications of these genome modification tools in gene therapy and other basic and applied science contexts.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-016-1047-x) contains supplementary material, which is available to authorized users.

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          Most cited references120

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          Inducible apoptosis as a safety switch for adoptive cell therapy.

          Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
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            In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.

            A retroviral vector system based on the human immunodeficiency virus (HIV) was developed that, in contrast to a murine leukemia virus-based counterpart, transduced heterologous sequences into HeLa cells and rat fibroblasts blocked in the cell cycle, as well as into human primary macrophages. Additionally, the HIV vector could mediate stable in vivo gene transfer into terminally differentiated neurons. The ability of HIV-based viral vectors to deliver genes in vivo into nondividing cells could increase the applicability of retroviral vectors in human gene therapy.
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              Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.

              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.
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                Author and article information

                Contributors
                josevargas123@gmail.com
                leochicaybam@gmail.com
                rstein@pucrs.br
                atanuri@biologia.ufrj.br
                andrescanedo@unipampa.edu.br
                +55 21 32076547 , mbonamino@inca.gov.br
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                12 October 2016
                12 October 2016
                2016
                : 14
                : 288
                Affiliations
                [1 ]Centro Infantil-Pontifícia Universidade Católica do Rio Grande do Sul-PUCRS, Porto Alegre, Brazil
                [2 ]Programa de Carcinogênese Molecular, Instituto Nacional de Câncer (INCA), Rua Andre Cavalcanti 37/6º andar, Centro, Rio de Janeiro, 20231-050 Brazil
                [3 ]Vice-presidência de Pesquisa e Laboratórios de Referência, Fundação Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
                [4 ]Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
                [5 ]Grupo de estudo de Expressão Gênica de Eucariotas, Unipampa, Sao Gabriel, Brazil
                Author information
                http://orcid.org/0000-0002-4416-5822
                Article
                1047
                10.1186/s12967-016-1047-x
                5059932
                27729044
                3e3db02d-4ba5-4510-b590-6eb5c49367d2
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 May 2016
                : 3 October 2016
                Funding
                Funded by: CNPq and FAPERJ Scholarships
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                Medicine
                gene therapy,lentivectors,transposons,clinical trials
                Medicine
                gene therapy, lentivectors, transposons, clinical trials

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