Recent trends in the gene therapy of beta-thalassemia

The beta-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult beta-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for beta-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from beta-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in beta-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for beta-thalassemia model systems; for beta-, gamma-, and anti-sickling beta-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of beta- globin and genome editing using designer nucleases.