The First CRISPR-Based Treatment Is Approved in the UK for Sickle Cell Disease and Thalassemia

An exciting medical development has taken place in the United Kingdom: sickle cell anemia and beta thalassemia are among the genetic blood disorders covered by the world's first approved gene-editing treatment using CRISPR.

This approval marks a medical milestone by enabling CRISPR technology to be used in people older than 12. The technology precisely cuts and edits genetic material, an achievement recognized with a Nobel Prize. Stem cells collected from patients are specially edited with CRISPR in the laboratory and then returned to them. This was shown to free patients from adverse effects of genetic blood disorders such as sickle cell disease and beta thalassemia for at least 12 months.

The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved Casgevy, which uses the gene-editing tool CRISPR, on 15 November 2023. The gene-editing technology CRISPR was recognized with a Nobel Prize in 2020.

What Is Beta Thalassemia?

Beta thalassemia involves mutations in the beta-globin subunit that reduce normal hemoglobin and red blood cells, causing insufficient oxygen delivery to the body. It is an inherited blood disease.

Beta thalassemia is one cause of anemia, or a low red blood cell level. Reduced red cell levels can cause dizziness, weakness, fatigue, bone abnormalities, and more serious complications.

Beta thalassemia is a preventable blood disease inherited from parents. It is an important public health problem in Mediterranean countries, including Turkey. Although carrier identification, genetic counseling, and prenatal diagnosis can prevent it, at least 365000 people with thalassemia are born and treated worldwide every year. Turkey has approximately 1300000 carriers and around 4500 patients.

Beta thalassemia is a severe disease that substantially shortens life and greatly reduces quality of life if treatment is not maintained properly. Treatment is difficult and very expensive. Annual treatment costs are approximately 10 thousand dollars per patient. Preventing the birth of affected individuals is therefore important, and the state also supports necessary preventive measures.

Transfusion-dependent beta thalassemia, the most severe form, generally requires lifelong red blood cell transfusions as standard treatment. These regular transfusions can themselves cause complications, including problems in the heart, liver, and other organs due to excess iron accumulation.

Related topic: The First Cell-Based Gene Therapy for Beta Thalassemia Received FDA Approval in August 2022

What Is Sickle Cell Anemia?

Sickle cell anemia—more accurately called “sickle cell disease” medically—is an inherited blood disorder caused by beta-globin gene mutations. These lead to abnormal hemoglobin, causing red blood cells to stiffen, become sickle-shaped, and block blood vessels. Patients experience acute pain, acute chest syndromes, and organ damage, all of which shorten life expectancy.

Casgevy's Approval Process

Clinical trials found that Casgevy restored healthy hemoglobin production in most participants, easing symptoms. No serious safety concern was identified during treatment, and safety continues to be closely monitored. The treatment involves genetically editing stem cells collected from the patient's bone marrow in the laboratory and then reinfusing them.

This gene-editing treatment was developed by Vertex Pharmaceuticals and CRISPR Therapeutics and commercialized under the Casgevy brand.

How Does It Work?

This one-time treatment uses CRISPR to edit the BCL11A gene locus in stem cells collected from the patient's bone marrow, increasing production of fetal hemoglobin (HbF). In sickle cell disease and beta thalassemia, fetal hemoglobin carries oxygen in place of abnormal adult hemoglobin (HbA). This may reduce disease severity and improve symptoms.

Why Was the BCL11A Gene Chosen?

BCL11A suppresses gamma (γ)-globin expression and fetal hemoglobin (HbF) production in adult erythrocytes. Therapeutic strategies aim to increase HbF to reduce the severity of sickle cell disease (SCD) and beta thalassemia (β-thalassemia). Suppressing BCL11A raises HbF levels, particularly in SCD, and reduces the distortion of hemoglobin associated with sickling. It is therefore considered the best approach to gene therapy for SCD.

Downregulation of BCL11A—reducing its activity—is considered a promising strategy for inducing HbF and is being applied in SCD and β-thalassemia. Differences in fetal hemoglobin levels persisting into adulthood may affect syndrome severity. BCL11A is a critical regulator of HbF suppression, and its pathogenic variants have provided insights into increasing HbF production and thereby easing disease severity.

Clinical Trial Results

Casgevy's approval is based on results from a study involving 45 sickle cell disease patients, with findings from 29 of them. Almost all of these patients were free from severe pain crises for at least 12 months after treatment.

In the beta thalassemia trial, 42 of 54 patients remained in the study long enough for the primary interim efficacy analysis. Of these eligible patients, 39 did not need red blood cell transfusions for at least 12 months after treatment. The remaining three had a reduction of more than 70% in transfusion requirements.

Reported side effects included nausea, fatigue, fever, and an increased infection risk. These resemble problems seen with other autologous stem cell transplants. No serious side effects were reported in the studies.

The MHRA decision grants Casgevy a one-year provisional marketing authorization, renewable annually provided real-world data and postmarketing studies continue to support its use.

This approval demonstrates gene editing's potential in medical treatment and may open the door to wider use of such therapies.