First CRISPR/Cas9 Gene Therapy Approved for Market

The first gene therapy utilizing CRISPR/Cas9 technology has received approval for clinical use, offering a groundbreaking treatment option for patients suffering from ?-thalassemia and sickle cell disease. This innovative therapy, known as Casgevy, aims to reactivate fetal hemoglobin production, which typically ceases after birth.

?-thalassemia and sickle cell disease are rare genetic disorders caused by mutations that disrupt the production or function of hemoglobin, the protein in red blood cells responsible for oxygen transport. In ?-thalassemia, there is a deficiency in ?-chains of hemoglobin, leading to anemia and a dependence on frequent blood transfusions for severely affected patients. Sickle cell disease, on the other hand, causes red blood cells to take on a crescent shape, which can block blood vessels and trigger painful crises in various parts of the body.

Traditionally, the only curative treatment option for these conditions has been hematopoietic stem cell transplantation from a compatible donor. However, finding a suitable donor is often challenging, and there are significant risks involved, including transplant rejection and graft-versus-host disease, which can be life-threatening. The introduction of Casgevy presents a personalized approach to treatment by utilizing the patient's own blood stem cells.

In this process, stem and progenitor cells are harvested from the patient and subjected to ex vivo treatment with the CRISPR/Cas9 gene-editing tool. This technique allows for targeted editing of a specific regulatory enhancer segment of the BCL11A gene. Following this gene editing, patients undergo high-dose chemotherapy to clear their bone marrow of existing stem cells, after which the modified cells are reinfused into the patient.

BCL11A plays a crucial role as a transcription factor that inhibits the expression of ?-globin, a component of fetal hemoglobin (HbF). By editing the BCL11A gene, the production of HbF is reactivated, leading to increased levels of this beneficial hemoglobin variant.

Casgevy (exagamglogen autotemcel) is now approved for treating transfusion-dependent ?-thalassemia in patients aged 12 and older who are eligible for stem cell transplantation but lack a compatible donor. Additionally, it is authorized for use in patients with severe sickle cell disease who experience recurrent vaso-occlusive crises and are also suitable for stem cell transplantation without an available matched donor.