Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

Abstract

Genome editing produces genetic modifications in somatic cells, offering novel curative possibilities for sickle cell disease and β-thalassemia. These opportunities leverage clinical knowledge of hematopoietic stem cell transplant and gene transfer. Advantages to this mode of ex vivo therapy include locus-specific alteration of patient hematopoietic stem cell genomes, lack of allogeneic immune response, and avoidance of insertional mutagenesis. Despite exciting progress, many aspects of this approach remain to be optimized for ideal clinical implementation, including the efficiency and specificity of gene modification, delivery to hematopoietic stem cells, and robust and nontoxic engraftment of gene-modified cells. This review highlights genome editing as compared to other genetic therapies, the differences between editing strategies, and the clinical prospects and challenges of implementing genome editing as a novel treatment. As the world's most common monogenic disorders, the β-hemoglobinopathies are at the forefront of bringing genome editing to the clinic and hold promise for molecular medicine to address human disease at its root.