Gene therapy and gene editing strategies for hemoglobinopathies

Abstract

Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with an integrating lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Studies and safety works demonstrated the potential therapeutic efficacy and safety of this approach, providing the rationale for clinical translation. The outcomes of early clinical trials, although showing promising results, have highlighted the current limitations to a more general application. These include the nature, source and age of repopulating hematopoietic stem cells, the suboptimal transduction efficiency and gene expression levels, the toxicity and efficacy of bone marrow conditioning, the stress status of bone marrow microenvironment in chronic diseases such as β-thalassemia and sickle cell disease. Recently, gene editing strategies based on the use of nucleases offered a novel approach to increase globin expression in a quasi-physiological way, independently from the addition of transgenes and viral sequences to the human genome. This review will discuss the current status of gene therapy for β-thalassemia and sickle cell disease with a perspective towards the improvements necessary in the context of clinical translation.