Regulatory approvals for first gene therapy based on CRISPR technology
In a significant development for medical science, the year 2023 concluded on a high note in the field of advanced therapies. For the first time ever, regulatory approvals were granted for a gene therapy that is based on the gene-editing technology called CRISPR/Cas9. The innovative treatment, Casgevy (exagamglogene autotemcel) from Vertex Pharmaceuticals and CRISPR Therapeutics, is indicated for two rare genetic diseases: sickle cell disease and transfusion-dependent β-thalassemia. Here, we present how these regulatory decisions not only constitute a major hope for the patients suffering from these disorders, but also open new horizons in the application of precision gene-editing techniques for gene therapies on an international scale.
Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) both stem from genetic mutations that affect the function or production of haemoglobin – a vital protein in red blood cells responsible for delivering oxygen throughout the body. These two rare hereditary diseases share a commonality in their lifelong debilitating impact on the body’s oxygen-carrying capacities, and can be life-threatening.
SCD predominantly affects people of African and Caribbean origin. The error in the gene for haemoglobin causes the red blood cells to assume a crescent shape. The distortion of these cells impedes their smooth circulation in the blood vessels and thereby hinders the transport of oxygen to the body’s organs and tissues. This leads to a range of health problems including episodes of severe pain, anaemia and organ damage known as vaso-occlusive crises (VOCs).
TDT is more common in people of Mediterranean, south Asian, southeast Asian and Middle Eastern origin. It is characterised by an impaired production of haemoglobin so individuals with the condition experience severe anaemia due to ineffective erythropoiesis. Patients grappling with TDT therefore often rely on regular blood transfusions and medicines to alleviate symptoms.
On 15 November 2023, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) became the first regulatory body in the world to conditionally approve a medicine that uses the gene-editing CRISPR technique: Casgevy for the treatment of sickle cell disease and transfusion-dependent β-thalassemia . Following this transformative milestone, on 2 December 2023 the National Health Regulatory Authority (NHRA) made Bahrain the first Middle East country to provide approval of Casgevy for the same two medical conditions . Then, on 8 December 2023, the United States’s Food & Drug Administration (FDA) approved Casgevy as one of two gene therapies to treat sickle cell disease, ultimately making it the first gene-editing medicine to be licensed in the United States . The decision of the American regulatory authority on the use of Casgevy for the treatment of transfusion-dependent β-thalassemia is expected in March 2024. Lastly, on 14 December 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) delivered a positive opinion on Casgevy and recommended its conditional approval for the treatment of both blood disorders . The final approval decision by the European Commission is expected in the first trimester of 2024.
The approvals are indicated for 12-year-old patients and older suffering from SCD with recurrent VOCs or with TDT, who are eligible for a haematopoietic stem cell transplant but a donor is not available. As part of the approval processes, the safety and efficacy of Casgevy have been evaluated in clinical trials for both SCD and TDT. The therapy was shown to relieve debilitating episodes of pain in the former disease and to remove or reduce the need for transfusions for at least a year in the latter one.
At the heart of this revolutionary advancement is the utilisation of the CRISPR/Cas9 technology, an innovative precision gene-editing tool whose mechanism was described in a historic publication only 12 years ago  and whose discoverers, Jennifer Doudna and Emmanuelle Charpentier, were awarded the Nobel Prize in Chemistry in 2020.
CRISPR, an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, enables precise modifications to an organism’s DNA. It originates and was adapted from a naturally occurring genome editing system that bacteria use as an immune defence. It consists in a pair of molecular “scissors” that is capable of precisely cutting a specific DNA sequence under the guidance of a customable guide. This enables to accurately edit (add, remove or modify) DNA where it was cut. This sophisticated mechanism allows for the accurate alteration of genetic material, making CRISPR a powerful tool in the realm of gene editing.
Casgevy edits the defective gene in a patient’s bone marrow stem cells to induce functional haemoglobin production. The process involves the extraction of the bone marrow stem cells from the patient’s blood, their modification in the laboratory through CRISPR/Cas9 to be able to produce the foetal form of haemoglobin, and their reinfusion into the patient where they will start producing normal red blood cells. The patient requires chemotherapy prior to reinfusion so as to remove cells from the bone marrow that will be replaced with the CRISPR-edited ones.
CRISPR’s journey from basic research to the bedside has been rapid, with encouraging clinical results leading to its first regulatory approvals. Casgevy emerges as a promising therapy to impact the lives of patients grappling with SCD and TDT. It indeed holds the potential to bring about enduring improvements in patients’ wellbeing. The one-time, personalised nature of this gene-editing therapy offers the prospect of long-term efficacy where individuals burdened by these genetic blood disorders may experience a substantial alleviation of symptoms and a reduced frequency of medical interventions. Casgevy’s potential to address the root cause of these genetic disorders rather than merely managing symptoms signifies potentially providing a lifetime of improved health and quality of life for those currently facing the challenges posed by SCD and TDT.
Beyond its immediate applications, Casgevy has broader implications for the field of advanced therapies. The pioneering use of CRISPR/Cas9 technology in Casgevy opens doors to exploring its potential applications in treating a wide array of genetic diseases. The versatility of CRISPR/Cas9 as a gene-editing tool offers hope for developing targeted therapies for various genetic disorders, ushering in a new era of precision medicine where treatment approaches can be tailored to the unique genetic makeup of each patient. The prospect of extending the success witnessed with Casgevy to other genetic conditions holds tremendous potential for improving patient outcomes and advancing the frontiers of gene therapies.
However, this historic achievement also brings about discussion around the challenges that the gene-editing therapy entails. The intricacy of the treatment process itself, which involves blood stem cell extraction, gene editing as well as chemotherapy prior to reinfusion, relies on the availability of specialised resources and infrastructures. This introduces logistical complexities that demand careful consideration. The necessary step of chemotherapy, whose potential side effects include infertility, poses a difficult decision for eligible patients considering Casgevy. In addition, the anticipated high cost of the gene-editing therapy may be a further obstacle that hinders its affordability, ultimately affecting its integration into healthcare systems and thereby the availability of the innovative treatment to patients.
To conclude, Casgevy marks a transformative milestone and opens the door to new horizons in precision gene-editing therapy. As the field of gene therapy advances, a balanced approach that addresses these challenges will be essential to fully unlock the potential of Casgevy and similar precision gene-editing technologies. This will be paramount to enable effective adoption and widespread availability thereby maximising their impact and benefit for individuals facing serious genetic disorders.
Author: Clémence Foltz, Nicole Ticchi
 Martin Jinek et al., A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science 337, 816-821 (2012). DOI:10.1126/science.1225829
Advanced therapy, gene therapy, gene editing, CRISPR, regulatory approval