Hemoglobinopathies, including severe β-thalassemia and sickle cell disease, represent the
most common monogenic disorders worldwide. Allogeneic hematopoietic stem cell transplantation
(allo-HCT) is the only approved curative option for these syndromes, albeit limited to patients having
a suitable donor. Gene therapy, by making use of the patient’s own hematopoietic stem cells to introduce
a normal copy of the β-globin gene by viral vectors, bridged the gap between the need for cure of
patients with hemoglobinopathies and the lack of a donor, without incurring the immunological risks
of allo-HSCT. However, gene therapy for hemoglobinopathies proved a difficult and elusive goal for
decades and only recently, lenti-viral vector gene therapy was successfully transferred to the clinic.
Importantly, during the last years, additional curative options for patients with thalassemia and sickle
cell disease are being developed, based on the ability to manipulate the genome by employing programmable
nucleases and next-generation genome-modifying tools, thus providing the exciting prospects
of targeted in-situ gene correction. In this review, we will summarize current developments in
the new era of treatment for hemoglobinopathies, elaborate on lessons gained from gene therapy trials
and discuss the exciting prospects and challenges of genome editing.