In the United Kingdom, for the first time globally, a therapy based on the CRISPR/Cas9 gene-editing tool has been approved to address blood disorders. This method is employed in the treatment of sickle cell anemia and beta-thalassemia, both hereditary conditions causing pathological alterations in the blood pigment hemoglobin. However, it’s essential to note that CRISPR therapy does not rectify the underlying genetic defect. Instead, it reactivates the production of fetal hemoglobin, which then assumes the function of the defective blood pigment.
Both sickle cell anemia and beta-thalassemia result from a defect in the genetic blueprint for hemoglobin. Consequently, malformed or insufficient red blood cells are produced. This leads to severe anemia, and in the case of sickle cell anemia, it also causes pain and organ damage. Affected individuals require regular blood transfusions and medications throughout their lives, with long-term relief achievable only through a bone marrow donation and stem cell transplantation.
Scientists have been exploring the use of the CRISPR/Cas9 gene-editing tool against these blood disorders for several years. In 2016, a team successfully repaired the genetic defect of sickle cell anemia in human blood stem cells, albeit solely in a laboratory setting with subsequent re-implantation into mice. In 2015, Chinese researchers attempted to correct the thalassemia defect in human embryos, but with limited success. It is crucial to acknowledge that such interventions in the human germline raise ethical concerns, as evidenced by global criticism following these attempts.
Gene Therapy Reactivates Fetal Hemoglobin
The British Medicines and Healthcare products Regulatory Agency (MHRA) has recently granted approval for a gene therapy for two blood disorders based on CRISPR/Cas9 technology. This treatment, named Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, marks the first global approval of a gene therapy using the CRISPR/Cas gene-editing tool. Julian Beach from MHRA expressed satisfaction, stating, “I am pleased to announce the approval of an innovative and unprecedented gene therapy called Casgevy.”
However, it’s important to note that the Casgevy gene therapy does not repair the genetic defect causing the blood disorders. Instead, it reactivates the production of fetal hemoglobin, typically produced only in the fetal stage and in newborns. The CRISPR/Cas therapy achieves this by disabling a gene responsible for stopping fetal production. Consequently, fetal hemoglobin can assume the function of the diseased blood pigment, effectively curing anemia.
The approval of the Casgevy gene therapy is based on clinical studies involving 45 patients with sickle cell anemia and 54 patients with beta-thalassemia. Initially, hematopoietic stem cells were extracted from their bone marrow, and in the laboratory, the corresponding gene was modified using CRISPR/Cas9. Meanwhile, patients undergo chemotherapy to largely eliminate the diseased hematopoietic stem cells in their bone marrow, creating space for the genetically edited stem cells to be engrafted.
Subsequently, patients receive their edited hematopoietic stem cells through infusion. These cells proliferate in the bone marrow, forming red blood cells that contain a high proportion of fetal hemoglobin. In the approval studies, 28 out of 29 sickle cell patients who completed the study were pain-free and did not require blood transfusions. In thalassemia, 39 out of 42 patients could completely abstain from blood transfusions, with the remaining needing only a third of the previous amount.
Regulatory authorities and the company anticipate the long-term efficacy of the gene therapy. However, the duration of this effect and the potential need for repeat treatments remain unknown.
Not a Replacement for Existing Therapies, but a Supplement
The major advantage of CRISPR therapy is that, unlike stem cell transplantation, it does not elicit an immune response from the recipient’s body leading to rejection, nor does it trigger an immune response from the donor. This is because the cells reintroduced into the body are the individual’s own. However, it is crucial to note that the actual genetic defect causing the inherited diseases is not repaired through this therapy. Therefore, treated patients can still pass on these genetic defects to their offspring.
Additionally, it is worth mentioning that gene therapy using Casgevy is as burdensome for patients as bone marrow donation and stem cell therapy. Furthermore, the therapy is associated with a considerable financial cost, exceeding two million euros per patient, in contrast to the maximum cost of 300,000 euros for stem cell transplantation. This financial aspect poses a significant challenge for healthcare systems. Consequently, CRISPR therapy is not expected to replace stem cell transplantation in the foreseeable future but rather serve as a complementary approach.
The approval process for CRISPR therapy is underway in various countries. In the United States, a decision on the approval of Casgevy for sickle cell anemia is expected in early December and for beta-thalassemia in the spring of 2024. The European Medicines Agency (EMA) has also initiated the evaluation of Casgevy gene therapy.