Gene Therapy Advances for Sickle Cell Disease

By: Vivian Hsu

On December 8, 2023, the FDA approved two groundbreaking treatments for patients with sickle cell anemia (SCD), a group of disorders that causes red blood cells to contort into a sickle shape. These treatments represent the first cell-based gene therapies for SCD in patients 12 years and older! Until recently, the only potential curative treatments for SCD were stem cell and bone marrow transplants. While these transplants can cure SCD, they are rarely recommended due to their high risks, including mortality. Moreover, these procedures are only recommended for people, usually children, with significant symptoms and complications of SCD.

The first treatment, Casgevy, is among the first FDA-approved therapies utilizing genome editing technology! It employs CRISPR/Cas9, a sophisticated genome editing technique, to modify patients’ hematopoietic (blood) stem cells. CRISPR/Cas9 preciously cuts out the gene responsible for SCD, enabling accurate editing of the DNA at the cut site. Subsequently, these modified cells are transplanted back into the patient through engraftment within the bone marrow. This process stimulates the production of fetal hemoglobin (HbF), a protein that enhances oxygen delivery. Increased HbF levels prevent red blood cell sickling.

The second treatment, Lyfgenia, uses a lentiviral vector to genetically modify the patient’s blood stem cells to produce HbAT87Q. This gene-therapy-derived hemoglobin functions similarly to normal adult hemoglobin found in individuals without SCD. HbAT87Q within red blood cells reduces the risk of sickling and subsequent blood flow obstruction. These modified stem cells are then transplanted back into the patient.

Both Casgevy and Lyfgenia are autologous therapies, meaning they utilize the patient’s own blood stem cells, which are modified and then reintroduced through hematopoietic stem cell transplant. Prior to treatment, patients undergo blood stem cell collection, followed by chemotherapy to create space in the bone marrow for the newly modified cells. Given their relative novelty, patients receiving these treatments are enrolled in long-term studies to assess their effectiveness and safety. Nevertheless, Casgevy and Lyfgenia represent significant advancements in the treatment of SCD, offering new hope to affected individuals.