Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders.

In the last few years, gene therapy, holding the promise for long-term disease correction through a one-time treatment, has transitioned from experimental research to approved medicine. Several gene therapies are now available for congenital blood disorders, notably for hemophilia and hemoglobinopathies. In this review, we discuss each of the six therapies that now have regulatory approval for treatment in the United States: Roctavian (valoctocogene roxaparvovec) for hemophilia A, Beqvez (fidanacogene elaparvovec) and Hemgenix (etranacogene dezaparvovec) for hemophilia B, Lyfgenia (lovotibeglogene autotemcel) for sickle cell disease, Zynteglo (betibeglogene autotemcel) for β-thalassemia, and Casgevy (exagamglogene autotemcel) for either sickle cell disease or β-thalassemia. The underlying principles for these treatments vary and include both in vivo and ex vivo methods, lentiviral and adeno-associated viral (AAV) vectors, and gene silencing by the CRISPR-Cas9 gene editing system. Consequently, they pose correspondingly disparate risks and benefits when compared to other treatment modalities and to each other. Although long-term effects are not yet entirely understood, given the novelty of these therapies, knowledge on patient outcomes is continuously increasing. Overall, results are very encouraging, often freeing patients from the need for coagulation factor or red blood cell (RBC) infusions, albeit that for some of these diseases there is room for further improvement in terms of safety and therapeutic durability, which may be achieved with next-generation gene therapy products. However, improvements are needed to address issues with durability of results, side effects, and accessibility of these therapies.