Studies of hemoglobin, and its associated disorders, sickle cell disease (SCD) and the thalassemias, have written much of the history of the development of molecular biology and genetic medicine. More than 70 years ago, Dr. Linus Pauling dubbed SCD the first “molecular disease,” and seven years later Dr. Vernon Ingram identified the single amino acid difference between normal and sickle hemoglobin within the adult b-globin protein. With the advent of gene cloning and DNA sequencing, subsequent research in the 1980s elucidated the myriad mutations in the b-globin gene causing reduced or absent b-globin production in b-thalassemias. The benefits of increased expression of fetal hemoglobin (HbF) in individuals with SCD or b-thalassemia were recognized by astute clinicians based on of the lack of symptoms in the neonatal period and in the benign hereditary persistence of fetal hemoglobin (HPFH) condition. This stimulated interest in understanding the intricacies of globin gene regulation and how the switch from fetal (g)-to adult (b)-globin is normally controlled. In parallel, advances in gene transfer fueled efforts to introduce normal globin genes into hematopoietic stem cells of patients with mutant b-globin genes as curative therapy, an autologous approach built on decades of improvements in allogeneic bone marrow transplantation. Finally, remarkable advances in the modification of genes with CRISPR over the past decade have provided the means to define with precision the function of specific DNA sequences and develop gene editing approaches for therapy.

These research threads have converged to bring the first successive clinical trials forward for patients with SCD and b-thalassemia. In the last year, both globin gene addition (lovo-cel) and CRISPR gene editing (exa-cel) therapies received FDA approval. This lecture will describe the background and results of these groundbreaking studies, and discuss the challenges faced in bringing therapies to the many patients with SCD and b-thalassemia, particularly in resource-limiting geographic regions.

Dr. Stuart Orkin will describe current perspectives on the transcriptional control of globin genes, focusing on the direct role of the repressor protein BCL11A in silencing of HbF production and how CRISPR editing of an erythroid enhancer within the BCL11A gene forms the basis of the approved editing therapy, exa-cel, developed by CRISPR Therapeutics and Vertex Pharmaceuticals.

Dr. John Tisdale will summarize recent advances in ex vivo modification of hematopoietic stem cells for both lentiviral gene and CRISPR gene editing therapies for the hemoglobin disorders, concentrating on clinical parameters and prospects for improving preconditioning and moving toward strategies that would allow application without the need for hospitalization and intensive supportive care.