The first CRISPR treatment – Casgevy wins UK approval for sickle cell disease

In a world first, the UK medicines regulator has given the green light to a therapy employing CRISPR gene editing for the treatment of disease. Remarkably, this first regulatory approval comes just over a decade after Jennifer Doudna and Emmanuelle Charpentier published their ground-breaking paper in Science.

The approved therapy, Casgevy, which was developed by Vertex Pharmaceuticals and CRISPR Therapeutics, will treat the blood conditions sickle cell disease and β-thalassaemia, offering a potential breakthrough for those experiencing debilitating pain and requiring blood transfusions as a result of the diseases.

This approval is fantastic news and we are very proud to have been involved in protecting the revolutionary CRISPR technology. The very first patents to be granted to Jennifer Doudna and Emmanuelle Charpentier as inventors of this technology were at the UK and European Patent Offices, represented by a team of Mewburn Ellis attorneys. The Mewburn team helped secure grant of these first UK and European patents despite the applications coming under frequent attack by third parties, who filed a very large number of anonymous observations throughout examination in an attempt to derail grant (read this article for more about third party observations). The first European patent, EP2800811, has also since survived being attacked by seven parties in proceedings before the Opposition Division of the European Patent Office (read this article for more about the EPO oppositions procedure). Mewburn Ellis continues advise and represent applicants in this area of technology before the European Patent Office.

How does Casgevy work?

Casgevy utilises the gene-editing tool CRISPR, for the discovery of which Jennifer Doudna and Emmanuelle Charpentier won the Nobel Prize in Chemistry in 2020.

Both sickle cell disease and β-thalassaemia are the result of mutations in the DNA sequence of genes encoding haemoglobin, a crucial molecule which facilitates oxygen transport by red blood cells.

In sickle cell disease, abnormal haemoglobin distorts red blood cells and makes them abnormally sticky, causing the formation of clumps which obstruct blood vessels, leading to reduced oxygen supply to tissues. This reduced oxygen supply is what drives the severe pain associated with the disease.

The mutations in the haemoglobin gene causing β-thalassaemia lead to a reduction or elimination of the molecule in red blood cells, low numbers of red blood cells and symptoms including fatigue, shortness of breath and irregular heartbeats.

The Casgevy treatment uses an RNA molecule to guide a CRISPR-Cas9 complex to the correct region of DNA in the gene targeted by Casgevy, BCL11A. Once the Cas9 enzyme reaches BCL11A, it cuts both DNA strands. The function of BCL11A is to prevent the production in adults of a form of haemoglobin that is normally only made before birth (fetal haemoglobin), and which does not carry the same abnormalities as the adult form of haemoglobin in affected patients. Accordingly, the disruption of this gene by Casgevy allows the production of fetal haemoglobin in patients with sickle cell or β-thalassaemia.

The treatment process involves mobilising stem cells out of bone marrow and collecting them from the body of patients with either disease, before editing the genes encoding for haemoglobin in these cells using CRISPR. This is followed by intravenous infusion of the gene-edited cells back into the body, which give rise to red blood cells containing fetal haemoglobin, providing relief of symptoms associated with the diseases by boosting the oxygen supply around the body. 

In the two global clinical trials of Casgevy, 28 out of 29 sickle cell patients were free of severe pain and 39 of 42 beta thalassaemia patients no longer needed blood transfusions for at least a year.

Looking forward – the first of many approvals?

The U.S. Food and Drug Administration (FDA) is also considering approval of Casgevy, with a scheduled decision date of December 8. The FDA is expected to follow suit by approving the treatment, following a meeting of advisors last month. The European Medicines Agency is also currently reviewing Casgevy for the treatment of both sickle cell and β-thalassaemia. Bluebird bio’s lovo-cel is another CRISPR-based treatment for sickle cell disease up for approval in the US with a decision expected later in December.

This initial approval appears almost certain to pave the way for many other CRISPR-based therapeutics, as evidenced by the fact that the number of clinical trials using CRISPR is now more than double the number of clinical trials using TALEN, ZFN, and other gene editing methods combined, according to the Alliance for Regenerative Medicine. In addition to gene therapy, CRISPR has been widely adopted by developers in the cell therapy space to devise improvements to CAR-T, Natural Killer, and other cell therapies.

The toolbox of different types of CRISPR-based gene editing available to researchers is also expanding at a pace. Technologies such as base editing and prime editing harness the advantageous specificity and ease of programmability of CRISPR while enabling distinct types of gene modification. With base editing already being used in clinical trials, we may not have long to wait before another landmark approval for a new form of CRISPR-based therapy.