How Casgevy Works: CRISPR Therapy for Sickle Cell Disease

Casgevy was the first therapy approved that uses CRISPR-Cas9 gene editing. The striking part: it does not repair the gene that causes the disease. Instead it switches a backup system — one the body used in infancy — back on.

The problem: a single-letter change in HBB

Sickle cell disease and beta-thalassaemia are caused by mutations in HBB, the gene encoding the beta chain of adult haemoglobin. In sickle cell disease a single base change makes haemoglobin molecules stick together under low oxygen, deforming red blood cells into a sickle shape. Those cells block vessels, causing pain crises, tissue damage and organ complications.

In beta-thalassaemia, too little beta chain is produced at all, leading to severe anaemia and, for most patients, a lifetime of blood transfusions.

The idea: bring back infant haemoglobin

Before birth and shortly after, the body makes a different haemoglobin: fetal haemoglobin (HbF). HbF does not need the HBB gene — it uses a gamma chain instead. In the months after birth a switch shuts that production down and adult haemoglobin takes over.

A gene called BCL11A sits at the centre of that switch. A long-standing clinical observation: sickle cell patients who naturally retain high fetal haemoglobin have markedly milder disease. Casgevy targets exactly this — it leaves the faulty HBB gene untouched and instead disables the erythroid-specific regulatory region of BCL11A, so fetal haemoglobin production restarts.

Rather than repairing the broken gene, reopen the alternative the body already has.

The treatment, step by step

1. The patient's own blood stem cells are collected by apheresis.
2. The cells are edited in the laboratory with CRISPR-Cas9, targeting BCL11A's erythroid enhancer region.
3. The patient receives conditioning chemotherapy to make room for the edited cells — the heaviest and riskiest step of the process.
4. The edited stem cells are infused back into the patient.
5. The cells engraft in the bone marrow and begin producing red cells rich in fetal haemoglobin.

What we still do not know

• Long-term durability: whether the edited cells keep working over decades is still being followed.
• Off-target editing: no significant signal has been reported in analyses, but long-term monitoring continues.
• Access: the therapy is extremely expensive and available only at a limited number of centres.

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