What Is Gene Therapy for Sickle Cell Disease? How CRISPR Works, Who May Benefit and What to Know

For decades, treatment for sickle cell disease has largely focused on preventing complications, managing pain, and reducing damage caused by the condition. Now, gene therapy is changing the conversation.

In 2023, the UK became the first country to authorise Casgevy (exagamglogene autotemcel), a treatment that uses CRISPR gene-editing technology to alter a patient's own blood stem cells. The treatment was subsequently recommended by NICE for certain people with severe sickle cell disease through a managed access programme in England

The development is significant because gene therapy does not simply treat the symptoms of sickle cell disease. It aims to alter the biology that causes red blood cells to sickle in the first place.

What Is Sickle Cell Disease?

Sickle cell disease is an inherited blood disorder caused by genetic changes affecting haemoglobin, the protein in red blood cells responsible for carrying oxygen.

In people with the condition, abnormal haemoglobin can cause red blood cells to become rigid and take on a characteristic sickle or crescent shape. These cells can block small blood vessels, restricting blood flow and oxygen delivery.

The resulting vaso-occlusive crises (VOCs) can cause severe pain and may contribute to organ damage and other serious complications.

The condition affects approximately 17,500 people in the UK. It is particularly common among people with African and Caribbean heritage, although it occurs in other populations too.

What Is Gene Therapy?

Gene therapy is a broad term for treatments that modify genetic material or alter the biological properties of cells to treat disease.

It does not necessarily mean replacing an entire faulty gene with a healthy one. Different gene therapies work in different ways, including adding genetic material, switching genes off, or changing the behaviour of cells.

For sickle cell disease, one of the most important developments is gene editing, where scientists make a targeted change to a patient's genetic material.

Casgevy is currently the most prominent example.

How Does Casgevy Work?

Casgevy uses CRISPR/Cas9, a gene-editing technology that allows scientists to make a targeted change to DNA.

Rather than directly correcting the genetic mutation responsible for sickle cell disease, Casgevy edits a regulatory region of a gene called BCL11A in blood stem cells. This reduces BCL11A activity in developing red blood cells and increases production of foetal haemoglobin (HbF).

Why Does That Matter?

Foetal haemoglobin is naturally produced before birth and does not have the same sickling behaviour as the abnormal haemoglobin associated with sickle cell disease. Increasing HbF can therefore reduce the tendency of red blood cells to sickle.

The goal is to produce blood cells that are much less likely to cause the blockages responsible for painful VOCs.

What Happens During the Treatment?

Casgevy is not simply an injection that changes someone's DNA inside their body.

First, blood stem cells are collected from the patient. These cells are then sent to a laboratory, where CRISPR/Cas9 is used to edit them.

The modified cells are subsequently returned to the patient through an intravenous infusion. Before this happens, the patient receives myeloablative conditioning chemotherapy to clear space in the bone marrow for the modified stem cells to establish themselves.

This makes the treatment considerably more involved than the phrase 'one-off gene therapy' might suggest. Although Casgevy is administered as a single infusion, the overall treatment process involves stem-cell collection, laboratory processing, chemotherapy, infusion, and extended follow-up.

How Effective Is Gene Therapy for Sickle Cell Disease?

The early results have been striking, although they need to be interpreted carefully because the studies were relatively small and did not compare Casgevy directly with another treatment.

In the clinical trial supporting US approval, 44 people received Casgevy. Among the 31 patients who had enough follow-up to be assessed for the primary outcome, 29 (93.5%) were free from severe VOCs for at least 12 consecutive months within the specified follow-up period.

The MHRA reported similarly encouraging results when it authorised the treatment in the UK. Of 29 patients eligible for the primary interim analysis, 28, or 97%, were free of severe pain crises for at least 12 months following treatment.

Those numbers are promising, but they do not mean every person treated will be permanently free of sickle cell complications.

The studies are ongoing, and researchers are continuing to monitor patients to establish how durable the benefits are and what long-term risks may emerge. NICE has specifically highlighted uncertainty about the treatment's long-term effectiveness.

Who Can Receive Casgevy on the NHS?

Casgevy is not currently an option for everyone with sickle cell disease.

In England, NICE recommends it through managed access for people aged 12 and over who have severe sickle cell disease with recurrent VOCs, certain sickle cell genotypes, and for whom a haematopoietic stem-cell transplant is appropriate but a suitable matched related donor is unavailable.

Patients must generally have experienced at least two VOCs per year during the previous two years to meet the NICE criteria. The managed access arrangement exists because more evidence is still being collected. NICE has said it will reassess the treatment when additional evidence becomes available.

What Are the Risks and Limitations?

The promise of gene therapy should not obscure the intensity of the treatment.

The chemotherapy required before Casgevy can cause significant side effects and suppress the bone marrow. Reported adverse effects include nausea, headache, and muscle and bone pain, while the treatment process can also involve complications associated with stem-cell collection and conditioning.

Fertility is another important consideration. The UK product information states that infertility has been observed with myeloablative conditioning, meaning fertility-preservation options should be considered where appropriate.

There is also the fundamental question of how long the benefits will last. Casgevy's effects are expected to be long-lasting after successful engraftment, but researchers are still gathering long-term human data. Patients receiving the treatment are therefore followed over an extended period.

Could Gene Therapy Change Sickle Cell Treatment?

Casgevy represents a major shift from managing the consequences of sickle cell disease towards modifying the patient's blood-forming cells to reduce the underlying biological problem.

But it would be premature to call gene therapy a universal cure. Access remains limited, the treatment is intensive and expensive, and questions about long-term effectiveness and safety remain.

For people with severe sickle cell disease who meet the eligibility criteria, however, the technology represents something that was previously difficult to imagine: a one-time treatment capable of dramatically reducing the painful crises that can dominate life with the condition.

As more patients are treated and followed for longer, researchers should gain a clearer picture of whether gene editing can deliver what sickle cell patients and clinicians have long hoped for: a durable, potentially life-changing alternative to lifelong disease management.