Gene Editing in Hematology (Casgevy, Lyfgenia)

Abstract

Hemoglobinopathies, such as sickle cell disease (SCD) and \beta-thalassemia, are common genetic disorders affecting millions worldwide, caused by issues in hemoglobin biosynthesis. Until recently, treatment options were mainly limited to palliative care and allogeneic hematopoietic stem cell transplant (HSCT), which has challenges like finding compatible donors and immunological risks. Breakthrough Gene Therapies In 2023, the U.S. Food and Drug Administration (FDA) approved two groundbreaking gene therapies for SCD, marking a significant advance in medical treatment: * CASGEVY (exagamglogene autotemcel): Also approved for transfusion-dependent \beta-thalassemia in individuals aged 12 and older. * LYFGENIA (lovotibeglogene autotemcel). Both therapies are autologous hematopoietic stem cell-based gene therapies and were approved for individuals aged 12 years and older with SCD who experience recurrent vaso-occlusion crises (VOCs). Comparison of Casgevy and Lyfgenia | Feature | Casgevy (Exagamglogene Autotemcel) | Lyfgenia (Lovotibeglogene Autotemcel) | |---|---|---| | Mechanism | A cell-based gene therapy using CRISPR/Cas9 technology for gene editing. | A cell-based gene therapy utilizing a lentiviral vector as a gene delivery vehicle. | | Effect | By silencing erythroid-specific BCL11A enhancer, the goal is to increase the production of Fetal Hemoglobin (HbF), which inhibits the polymerization of sickle hemoglobin (HbS). | By delivering an engineered hemoglobin containing the missense HBB 87T>Q variant (a novel \text{HbA}^{\text{T87Q}} variant) which has anti-sickling properties similar to normal adult hemoglobin (HbA). | | Efficacy | 29 out of 30 individuals (97%) achieved freedom from severe VOCs in an ongoing clinical trial (NCT03745287) after at least 12 consecutive months of follow-up. | 28 out of 32 (87.5%) participants achieved freedom from VOCs during follow-up (6 to 18 months) in the Phase 1/2 clinical trial (HGB-206). | | Adverse Effects | Common effects include leukopenia, thrombocytopenia, neutropenic fever, mouth sores, nausea, vomiting, abdominal pain, musculoskeletal pain, headache, and itching. | Common effects include stomatitis, leukopenia, anemia, thrombocytopenia, and febrile neutropenia. Acute myeloid leukemia has occurred in individuals treated with Lyfgenia, resulting in an FDA boxed warning. | | Comment | The first FDA-approved gene therapy utilizing CRISPR/Cas9. Does not contain a boxed warning for prescribers. | Individuals may be at risk of developing hematologic malignancies and are recommended to undergo lifelong monitoring. | Significance These FDA-approved gene therapies, Casgevy and Lyfgenia, represent a potential cure for SCD, offering a promising alternative to bone marrow transplantation. The approval of Casgevy highlights the potential of the CRISPR/Cas9 gene editing system, although concerns remain regarding potential genotoxicity and long-term safety of CRISPR-induced double-strand breaks (DSBs). These advancements are expected to accelerate research in cell-based therapies for genetic disorders globally.