The UK Medicines and Healthcare products Regulatory Agency (MHRA) approved CASGEVY™ for the treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) on 16 November 2023. This is the world’s first approval of a therapy using CRISPR/Cas9 gene-editing technology. We explore this historic development in this article.
CRISPR/Cas9 gene-editing technology
The CRISPR/Cas9 system was discovered a little over ten years ago. This gene-editing technique is often described as genetic scissors due to the ability of the system to cut genetic material in organisms and to edit the genome. While a number of gene-editing techniques were emerging at that time, the elegance and precision of CRISPR/Cas9 caused much excitement in the scientific community. Emmanuelle Charpentier and Jennifer Doudna published their discovery of the CRISPR/Cas9 system in Science in 2012 and went on to share the 2020 Nobel Prize in Chemistry for their discovery just eight years later.
In the years following the CRISPR/Cas9 discovery, several research groups worked with the gene‑editing tool to demonstrate its effectiveness and discover specific applications of the tool. Amongst them, Drs. Daniel Bauer and Stuart Orkin at the Boston Children’s Hospital discovered that certain regions in the BCL11A enhancer region held the key to regulating fetal hemoglobin (HbF) and identified a set of single guide RNA (sgRNA) sequences useful in producing an enrichment of HbF. Increasing HbF is a key mechanism in potential treatments for sickle cell disease and beta thalassemia, two severe monogenic diseases with severe and potentially life-threatening manifestations.
This discovery formed part of the development by Vertex and CRISPR Therapeutics of the therapy initially known as CTX001 and now known as exagamglogene autotemcel [exa-cel] or CASGEVY™.
The approval of this therapy is a significant milestone, and there are two aspects that are particularly striking. First, the time taken from the discovery of the CRISPR/Cas9 gene editing tool in 2012 to the first approval of a therapy using this tool in 2023 is remarkable. The development and approval of therapeutics is a long and uncertain process and so the speed at which CASGEVY has come to market is particularly noteworthy. Second, the clinical trial results showed very positive outcomes for almost all of the patients. 28 out of 29 sickle cell patients were free of severe pain and 39 of 42 beta thalassemia patients no longer needed blood transfusions for at least a year in the two global clinical trials of CASGEVY™.
Approval of CASGEVY™ in the US and Europe is expected in the coming weeks and months based on these results.
The first of many approved CRISPR gene-editing therapies?
There is great hope that the approval of CASGEVY™ will pave the way for many more therapies using CRISPR gene-editing to treat unmet patient needs. Many will hope that the speed and success of the approval of CASGEVY is, in part, related to the precision of the CRISPR technique itself such that other therapies will have a good chance of success.
The team at HLK are excited to follow this new dawn in therapeutics and to hopefully see many new CRISPR gene-editing treatments come to market. Our team is also proud and privileged to work on the European patent protecting this discovery by Drs. Bauer and Orkin.