Editing blood disorders

Abstract

Gene Therapy The two most common monogenic diseases, transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), result from mutations in the hemoglobin β-subunit gene ( HBB ), which is an essential element of adult hemoglobin A (α2b2). Current therapies for TDT and SCD are limited and do not address their underlying causes. Frangoul et al. report the treatment of two patients (one with TDT and the other with SCD) using gene therapy. After myeloablation, the patients were infused with their own hematopoietic stem and progenitor cells subjected to CRISPR-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A. This transcription factor represses the expression of γ-globin, a component of α2γ2 fetal hemoglobin that is known to ameliorate the severity of these disorders. More than a year later, both patients showed sustained engraftment of edited cells in the blood and bone marrow and increased fetal hemoglobin expression, which relieved symptoms and obviated the need for transfusions. N. Engl. J. Med. 10.1056/NEJMoa2031054 (2020).