First Approval for Use of Gene Editing for the Treatment of Haemoglobin Disorders
I previously blogged about the exciting development of the new technique of gene editing for the treatment of sickle cell disease (Gene Editing for the Treatment of Sickle Cell Disease. 1st March 2022). In a world first, the UK Medicines Regulatory Agency has now approved this procedure. This approval also covers use in the related disease of β-thalassaemia.
Both conditions are inherited diseases affecting the production of the blood protein β-haemoglobin. They are comparatively common in people whose ancestry arose in the Mediterranean, Middle East, Africa or Asia. The explanation is that these regions, at least historically, where affected by malaria. Although the mutations causing sickle cell disease and β-thalassaemia are harmful under normal conditions, they do give some protection from malaria.
These two disease cause a great deal of suffering. Current treatment options for both conditions are limited and cannot fully protect from long term complications, so patients face shortened life expectances.
The new gene editing treatment uses the recently developed editing tool CRISPR which enables pin-point changes to be made in a single gene. The discovery of CRISPR was awarded a Nobel Prize in 2020.
The licenced treatment, called Casgevy, involves taking a sample of the patient’s own bone marrow stem cells, and modifying them by CRISPR. The patient’s remaining bone marrow cells are then depleted, and the gene edited cells are returned. The patient is likely to need a hospital stay of a month in a protected ward while the modified bone marrow regenerates to full activity. It is therefore not an easy treatment, nor does it come cheap. But set against it are the considerable costs of the current management and treatment of these conditions. Since it is only bone marrow cells which receive the gene editing, the edit will not be passed on to any children the patients may have after treatment.
Casgevy takes a subtle approach to tackling these diseases because it does not target the faulty β-haemoglobin gene directly. Instead it targets a controlling gene called BCL11A. In adults the β-haemoglobin chain is a major component of haemoglobin, the oxygen carrying protein. But in the foetus a further chain, γ, is found in its place: there is a γ to β switch at birth. It has long been known that those few individuals with sickle cell disease or β-thalassaemia who persist in producingγ beyond birth are spared the worst effects of these diseases. Some years ago it was discovered that the γ to β switch is controlled by the BCL11A gene. Casgevy disrupts BCL11A to block the switch away from γ, allowing its production to continue. thereby ameliorating the effects of the faulty β gene.
Of the 70 or so patients treated by Casgevy and followed up for a 12 month period, over 90% were free of disease episodes and had no need for additional treatment. This apparent cure represents a step change in their clinical management. They will continue to be monitored to find out how long these cures last. Also, although CRISPR is a very precise gene editing tool, does there remain a risk, however small, of it hitting the wrong target in the DNA? Given the marked benefits of Casgevy for these patients it seems a risk worth taking, but due to the extreme novelty of this approach, this needs to be monitored this carefully.
Following this first approval for the medical use of CRISPR can we look forward to more approvals for its use in other genetic diseases?
© CC Rider
29th Dec 2023
What's in our genes 