The UK’s regulator has approved the world’s first CRISPR–Cas9 gene editing therapy, which aims to cure sickle cell disease and transfusion-dependent β-thalassemia. Casgevy (exagamglogene autotemcel) is a first-of-its-kind treatment made by Vertex Pharmaceuticals and CRISPR Therapeutics in Zug, Switzerland. It comes just 11 years after Jennifer Doudna and Emmanuelle Charpentier invented the technology. The green light from the Medicines and Healthcare Products Agency represents a major scientific achievement for Vertex and CRISPR and a landmark for the biotech industry.

The approval sets the stage for US Food and Drug administration go-aheads expected on 8 December for sickle cell disease and for β-thalassemia on 30 March 2024. But even as these approvals could transform treatment, initially, only a very small number of patients are likely to benefit from this costly and complex therapy. The healthcare infrastructure needed to administer the autologous cell therapy is limited, and what’s more, some patients who are eligible to receive Casgevy may choose to wait, given the limited experience the community has had to date with this kind of therapy.

The UK’s decision to endorse Casgevy in sickle cell disease was based on an impressive ability to eliminate severe vaso-occlusive crises — painful inflammatory attacks, often requiring hospitalization — in 28 out of 29 trial participants eligible for evaluation. It remains to be seen whether the therapy will also reduce stroke and organ damage in the long term and, crucially, extend life expectancy. Its long-term safety profile is also unknown at this point. So far, in the trial participants who received the therapy, there has been no evidence of genotoxicity arising from the introduction of double-strand breaks in their DNA from the CRISPR technology, but that possibility cannot be definitively ruled out. Vertex will be enrolling patients from earlier sickle cell disease or β-thalassemia trials in a 15-year safety study to track malignancies, mortality and other disease- and treatment-related parameters.

In sickle cell disease, the oxygen-carrying protein in red blood cells, hemoglobin, is compromised. Healthy hemoglobin comprises two α-chains and two β-chains; patients carry a point mutation in the β-globin gene, which leads to a glutamate-to-valine substitution at position 6 of the β-globin chain. This change results in a structure that forms rigid polymers when oxygen is not bound, causing red blood cells to adopt a characteristic sickle or crescent shape.

Sickling red blood cells die more rapidly than their healthy counterparts, which curtails oxygen transport around the body. What’s more, the red blood cells’ unusual shape predisposes them to adhere to the walls of capillaries, leading to blockages in blood vessels, lack of oxygen in nearby tissues, and painful vasculo-occlusive crises, which in the lungs or in a cerebral artery can be life-threatening and require immediate blood transfusion. Organ damage is more gradual, but heart, lung and kidney disease are all major causes of early death in adult patients.

Casgevy does not fix the mutation in sickle cell disease. Instead, it is designed to compensate for the loss of adult hemoglobin by inducing fetal hemoglobin, the main oxygen carrier in the fetus, which is normally switched off shortly after birth. It does so by disrupting expression of BCL11A, an erythroid-specific enhancer, which represses transcription of the gene encoding γ-globin, which forms the tetrameric protein along with α-globin. With Casgevy, fetal hemoglobin expression surges, but the amounts in red blood cells can still vary widely. “Just because it’s there doesn’t mean it’s sufficient,” says Julie Kanter, director of the adult sickle cell clinic at the University of Alabama at Birmingham. The damaging effects of red blood cell sickling can continue, particularly if fetal hemoglobin levels, as a percentage of total hemoglobin, fall below 20%, a threshold considered protective.

Casgevy is targeted at patients’ CD34+ hematopoietic stem cells, which are isolated from the bone marrow. The CRISPR editing components are introduced in the lab by electroporation as a ribonucleoprotein complex, comprising a synthetic guide RNA and a Streptococcus pyogenes Cas9 endonuclease. Administering Casgevy is complicated by the impact of the disease on hematopoiesis in patients. They need to undergo blood transfusions for two months before cell mobilization and then two rounds of mobilization and apheresis. (In β-thalassemia, in contrast, no pre-treatment transfusions are needed, and a single round of mobilization and apheresis usually suffices.) To make room for the edited cells, patients also need to undergo busulfan-based myeloablative preconditioning, which is highly toxic.

Vertex has stated that it aims to recruit about 50 treatment centers in the United States, which would cover the patients it deems eligible for treatment — those aged 12 years or over with severe disease and recurrent attacks. The personnel overhead is substantial, and current treatment centers will take time to gear up. Kanter says her organization, at peak, will be able to administer Casgevy or Bluebird Bio’s lentiviral gene therapy lovotibeglogene autotemcel, if approved, to about 12 patients per year. But it will first need to hire several more people. Similar limitations apply on a broader scale. Kanter, who is also president of the National Alliance of Sickle Cell Centers, cites a survey it conducted among 51 members, 38 of which said they planned to offer gene editing and gene therapies to patients. But half of them will need another year to get ready.

Other existing therapies may prevail. For sickle cell disease, hematopoietic stem cell transplant (HSCT) is already an important treatment option. Allogeneic HSCT from matched sibling donors can be curative, but only a small minority of patients has a perfectly matched sibling who is also free from the condition. Haploidentical HSCT followed by cyclophosphamide therapy, which requires only a partial match between donor and recipient human leukocyte antigen loci, is an option that could reach a much wider population. What’s more, it does not require myeloablative therapy. At a cost of about $400,000, it is also substantially cheaper than genetic approaches. Given the pricing of other gene therapies, Casgevy could cost as much $2 million per patient.

But any conversation with patients about their treatment options must be fully transparent, says Michael Rutledge DeBaun, founder and director of the Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease at Vanderbilt University Medical Center. That includes weighing the pros and cons of undergoing high-risk treatment now or waiting for better alternatives. “Let’s be clear about what we’re offering and what we’re not offering to our patients,” he says. Children and adults with a poor near-term prognosis are the best candidates for new therapies. “I reject the notion for children that we should cure them before they have a bad outcome,” he says. He also thinks there will be further options, beyond this approval. “I’m cautiously optimistic that in the future — not today — we will have a range of therapeutic options that will have better results,” he says.

Most people with sickle cell disease do not have any such choices, however. The condition is most prevalent in sub-Saharan Africa, and most patients live in low-income countries. DeBaun has extensive experience working in Nigeria, as well as the United States. The most urgent issue in Nigeria is ensuring that all patients have access to hydroxyurea, an inexpensive drug that boosts fetal hemoglobin production and reduces the frequency of crises. It has been a mainstay of therapy in wealthier countries for several decades, but is still not widely available in Nigeria or in other African countries. Sadly for most patients, the arrival of revolutionary new gene and gene editing therapies will not make any real difference to the enormous burdens the disease imposes on them.