Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy

Abstract

Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials.

Keywords: Gammaretroviral vector; Gene editing; Gene therapy; Hematopoietic stem cells; Homologous recombination; Lentiviral vector; Site-specific endonucleases.