Abstract
Retroviral vector gene therapy is a promising approach to treating HIV-1. However, integrated vectors are mutagens with the potential to dysregulate nearby genes and cause severe adverse side effects. Leukemia has already been a documented severe adverse event in gene therapy clinical trials for the treatment of primary immunodeficiencies. These side effects will need to be reduced or avoided if retroviral vectors are to be used clinically for HIV-1 treatment. The addition of chromatin insulators to retroviral vectors is a potential strategy for reducing adverse side effects. Insulators have already been effectively used in retroviral vectors to reduce genotoxicity in pre-clinical studies. Here, we will review how insulators function, genotoxicity in gene therapy clinical trials, the design of insulated retroviral vectors, promising results from insulated retroviral vector studies, and considerations for the development of insulated retroviral treatment vectors for HIV-1 gene therapy.
Highlights
Gene therapy is a promising alternative treatment option for HIV
Clonal outgrowth has occurred in several trials for primary immunodeficiencies, X-linked severe combined immunodeficiency disease (SCID-X1), Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), and the hemoglobinopathy, β-thalassemia [12,17,48,49,50,51,52]. These genotoxic events have often led to adverse side effects that are attributable to insertional mutagenesis by the integration of the gene therapy vector (Table 1)
The genotoxic events observed in early SCID-X1 clinical trials led to worldwide recognition that genotoxicity is a major obstacle for retroviral hematopoietic stem cells (HSC) gene therapy
Summary
Gene therapy is a promising alternative treatment option for HIV. Retroviral vectors are the favored method for effectively delivering anti-HIV genes to T cells or hematopoietic stem cells (HSC). During the massive expansion and differentiation of HSCs to produce the human immune system, the therapeutic transgene is transmitted to all mature white blood cells This is important for T cell therapies where there is expansion of gene-modified T cells. For anti-HIV therapy, gene expression could include any number of anti-HIV transgenes such as the membrane associated HIV fusion inhibitor C46, a trans-activation response element (TAR) RNA decoy, anti-HIV shRNAs or miRNA cassettes to inhibit HIV replication, or any combination thereof. But but thethe number of studies cellsled have to surprisingly persistence of gene-modified number long-term engrafted cells areare expected totobebelower transplantation [8,9,10]. An integration event occurs near transcription start site, and an enhancer within the retroviral vector activates the promoter (Figure 1a).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
