First Ever FDA-Approved Gene Therapies for Patients with Sickle Cell Disease:

The world of cell and gene therapies is constantly evolving, and, as a result, more treatments are being developed for various diseases. Researchers have made great progress in developing a potential new cure for sickle cell disease, a debilitating blood disorder in which a hemoglobin mutation causes red blood cells to “sickle.”  Sickled red cells restrict blood flow to organs and tissues, resulting in severe pain and organ damage. Patients with sickle cell disease often require lifelong transfusions and frequent hospitalizations to manage the disease.

In December 2023, the US Food and Drug Administration approved two new cell-based gene therapies for sickle cell disease, Casgevy and Lyfgenia. These therapies are approved for patients with sickle cell disease age 12 years and older and have the potential to cure the disease at the genetic level.

Both treatments involve the collection of autologous hematopoietic stem cells, genetically altering those stem cells, and then engrafting the modified autologous stem cells back in the patient after myeloablation. A key step in these therapies is the genetic modification of the patient’s cells, meaning that red blood cell sickling is corrected at the DNA level.

Casgevy is the first-of-its-kind gene editing technology to receive FDA approval. It uses CRISPR technology to edit and “turn off” a repressor of fetal hemoglobin, which results in activation of fetal hemoglobin expression.  This allows functional fetal hemoglobin to resume being made instead of nonfunctional beta hemoglobin.  Fetal hemoglobin functions normally in these patients but is turned off after birth. Switching it back on is a way for their bone marrow to begin making healthy red blood cells that do not sickle.

Lyfgenia genetically modifies autologous stem cells using lentiviral vector transduction of a functional hemoglobin gene. Lentiviral vectors are gene delivery vehicles which modify the stem cells so that they can begin making normal adult hemoglobin that will result in non-sickled red cells.

These gene therapies showed great safety and efficacy in clinical trials. Casgevy had a 93.5% success rate in eliminating severe vaso-occlusive episodes, and Lyfgenia had a similarly high success rate as 88% of patients achieved complete resolution of vaso-occlusive events. Of note, there is a black box warning for Lyfgenia for blood cancer; patients receiving it should have lifelong monitoring for malignancy.  The FDA approval of these gene therapies represents a huge advancement in the field of cell and gene therapy and provides hope for a cure for many patients suffering with sickle cell disease.

FDA News Release, Dec 8, 2023: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease