Gene Editing For Genetic Blood Disorders Is Here

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In a world-first move, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has authorised a CRISPR gene-editing based medicine (Casgevy) for the treatment of two genetic blood disorders: sickle cell disease and transfusion-dependent beta thalassaemia. 

These disorders affect millions of people worldwide. They are caused by mutations in the gene for beta globin, one of the subunits of the haemoglobin protein responsible for carrying oxygen within red blood cells. In the case of sickle cell disease, this causes blood cells to deform into ‘sickle’ shapes under certain conditions, leading to various health problems like attacks of pain and increased risk of strokes. In beta-thalassaemia, mutations result in insufficient production of haemoglobin, leading to poor red blood cell function and many other health problems. Severe cases require regular blood transfusions (transfusion-dependent beta thalassaemia), but this can lead to a serious condition called transfusion iron overload.

For decades, the only permanent treatment for these diseases has been a bone marrow transplant, which requires a compatible donor and carries serious risks of complications.

How does the treatment work?

CRISPR-Cas9 gene editing, whose inventors won the Nobel Prize in 2020, can be used to precisely delete, insert, or replace sections of DNA within a living cell. Casgevy uses CRISPR-Cas9 to target the BCL11A gene, which is involved in suppressing the production of foetal haemoglobin (HbF). HbF is a form of haemoglobin that is normally present only in foetuses and newborns. It has a higher affinity for oxygen than adult haemoglobin, and can prevent the sickling or destruction of red blood cells. People with sickle cell or beta thalassemia who have naturally high levels of HbF tend to have milder symptoms and fewer complications.

The treatment process involves collecting the patient’s haematopoietic stem cells (the cells within the bone marrow that produce new blood cells), modifying them with CRISPR-Cas9 in the laboratory, and then infusing them back into the patient after a chemotherapy treatment that wipes out the existing bone marrow. The modified stem cells then repopulate the bone marrow and produce red blood cells with higher HbF levels.

What do clinical trial results show?

The clinical trials of Casgevy are still ongoing and more results will be published in time. So far, 29 sickle cell patients and 42 transfusion-dependent beta thalassaemia patients have been in trials long enough for the efficiency of the treatment to be analysed. In both cases the results have been very promising. All of them have shown increases in HbF levels and reductions in markers of hemolysis (the breakdown of red blood cells).

The most remarkable outcomes were that, 12 months post-treatment, vaso-occlusive crises (VOCs) were eliminated in 97% of patients with sickle cell disease, while the need for regular blood transfusion was eliminated in 93% of patients with beta thalassemia. VOCs are episodes of severe pain caused by the blockage of blood vessels by sickle-shaped red blood cells. They are the main cause of morbidity and mortality in sickle cell patients, and often require hospitalisation and opioid treatment. 

The treatment has also been well tolerated, with no serious adverse events related to the gene editing. The most common side effects have been those associated with the chemotherapy regimen, such as infections, low blood counts, and hair loss, which are expected to be temporary and manageable.

What does this mean for the future?

In addition to offering a one-time treatment for blood disorders, this approval could pave the way for other applications of CRISPR-Cas9 in treating genetic diseases. CRISPR-Cas9 is a versatile and adaptable technology that can be tailored to different targets and diseases, and is already revolutionising the field of medicine.

However, there are still many challenges ahead. Blood disorders are good candidates for this kind of therapy because the procedures for isolating, editing, and reintroducing haematopoietic stem cells into the bone marrow is already well established. Safely using gene editing techniques on most other cell types is much more challenging.

Cost can also be an issue, and becomes increasingly prohibitive for less common genetic conditions. While we don’t yet know how much Casgevy will cost, sickle cell and beta thalassaemia are both relatively common.