Abstract
Gene therapy using integrating retroviral vectors has proven its effectiveness in several clinical trials for the treatment of inherited diseases and cancer. However, vector-mediated adverse events related to insertional mutagenesis were also observed, emphasizing the need for safer therapeutic vectors. Paradoxically, alpharetroviruses, originally discovered as cancer-causing agents, have a more random and potentially safer integration pattern compared to gammaretro- and lentiviruses. In this review, we provide a short overview of the history of alpharetroviruses and explain how they can be converted into state-of-the-art gene delivery tools with improved safety features. We discuss development of alpharetroviral vectors in compliance with regulatory requirements for clinical translation, and provide an outlook on possible future gene therapy applications. Taken together, this review is a broad overview of alpharetroviral vectors spanning the bridge from their parental virus discovery to their potential applicability in clinical settings.
Highlights
Human gene therapy incorporating genome engineering to enhance cell functions has the potential to cure numerous life-threatening diseases, including severe combined immunodeficiencies and cancer.The evolutionary optimized ability to stably integrate DNA into cellular genomes makes retroviruses very attractive for permanent therapeutic cell modifications
Retroviruses have been developed into valuable tools for human gene therapy with the focus on vectors derived from gammaretroviruses and lentiviruses
This apparent contradiction was resolved with the provirus hypothesis published by Howard Temin in 1964: “The results presented here with Rous sarcoma virus (RSV) can be most explained by the following model: virus enters a cell and directs formation of a DNA containing the genetic information of the virus
Summary
Human gene therapy incorporating genome engineering to enhance cell functions has the potential to cure numerous life-threatening diseases, including severe combined immunodeficiencies and cancer. Retroviral vector integration into the target cell genome can cause insertional activation of cellular proto-oncogenes, potentially leading to serious adverse events such as leukemia. A few years later, Francis Peyton Rous described the cell-free transmission of chicken sarcoma [2,3] These groundbreaking discoveries indicated that cancer could be caused by viruses, a novel paradigm which was not widely accepted at that time. Howard Temin in 1964: “The results presented here with RSV can be most explained by the following model: virus enters a cell and directs formation of a DNA containing the genetic information of the virus This new DNA, the provirus [...], acts as a template for formation of new nucleic acid, RNA, for the virion” [8]. The mechanisms of insertional genotoxicity have been intensely studied and retroviral vector designs have been markedly improved, increasing the safety of human gene therapy
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