The UK approval of the CRISPR-Cas9 gene editing therapy Casgevy (exagamglogene autotemcel or ‘exa-cel’) for treating the inherited blood disorders sickle cell disease (SCD) or transfusion-dependent b-thalassemia is an historic scientific and clinical milestone. Coming barely more than a decade after the technology was invented, it represents a major achievement for its developers Crispr Therapeutics and Vertex Pharmaceuticals.
But this particular approval is largely of academic interest, as very few patients are likely to receive the therapy in the UK, which is averse to paying for high-cost innovative therapies. Cost is not the only barrier to getting this highly effective therapy to patients, though. The healthcare capacity needed to deliver it is limited. Patients need to undergo several blood transfusions before their hematopoietic (‘blood-forming’) stem and progenitor cells can be harvested and isolated. These cells are then subjected to genetic modification, which does not eliminate the disease-causing haemoglobin mutation but induces the cells to produce foetal haemoglobin, which is normally switched off shortly after birth. Before the patients can received their engineered cells, they need to undergo myeloablative conditioning, to suppress their residual hematopoietic stem cell compartment, in order to make room for the transplant.
For those who do gain access to the therapy, it is potentially transformative. Although only a limited number have so far received Casgevy during clinical trials, the vast majority became free of the painful vaso-occlusive crises that characterise SCD. These arise when the mutated haemoglobin in their red blood cells forms rigid polymers, causing the cells themselves to adopt a characteristic ‘sickle’ shape, which impairs their ability to circulate in small blood vessels, leading to blockages and a lack of oxygen for the nearby tissues. Similar beneficial effects were seen with another new treatment option, Bluebird Bio’s Lyfgenia (lovotibeglogene autotemcel or ‘lovo-cel’), which is a more classical gene therapy.
It will take some time to learn whether the elimination of vaso-occlusive crises will be accompanied by reductions in organ damage and stroke, two other major complications of SCD, as well as by improvements in lifespan. But these benefits will be limited to small numbers of patients in wealthy countries. The two approvals will have little impact on the global disease burden, as most patients living with these conditions are in low-income countries that cannot afford these expensive therapies. Sub-Saharan Africa has the largest prevalence of SCD, while b-thalassemia is most prevalent in South Asia, the Middle East, North Africa, and Southern Europe.
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