2023: First CRISPR Gene Therapy Approved (Casgevy) (2023)

Casgevy (exagamglogene autotemcel, exa-cel; Vertex Pharmaceuticals and CRISPR Therapeutics) became
the world's first CRISPR-based medicine to receive regulatory approval, authorised by the UK
Medicines and Healthcare products Regulatory Agency (MHRA) on 16 November 2023 for sickle cell
disease and transfusion-dependent beta-thalassaemia, followed by FDA approval in December 2023 for
both indications. The approval vindicated an entire research lineage from the discovery of CRISPR
in bacteria through the 2012 characterisation of Cas9 as a programmable nuclease to clinical
therapeutic application in a decade.

Casgevy's mechanism exploits a naturally occurring fetal haemoglobin (HbF) switch that is normally
silenced after birth by the transcriptional repressor BCL11A. Sickle cell disease and
beta-thalassaemia patients suffer from deficient or dysfunctional adult haemoglobin but retain
latent capacity to produce HbF, which can functionally compensate. The therapy uses CRISPR-Cas9
to disrupt an erythroid-specific enhancer of BCL11A within autologous haematopoietic stem cells
(HSCs), permanently de-repressing HbF expression in red blood cell precursors. Edited HSCs are
reinfused after myeloablative conditioning, reconstituting the marrow with cells that produce
therapeutically sufficient HbF levels.

In the pivotal trials, 29 of 29 patients with transfusion-dependent beta-thalassaemia who received
Casgevy achieved transfusion independence, and 28 of 29 sickle cell disease patients were free
from severe vaso-occlusive crises for at least 12 months of follow-up—remarkable results for
diseases with limited disease-modifying options.

The drug's list price of $2.2 million per patient in the United States made it the most expensive
single treatment ever approved at launch, intensifying global debate about the pricing of curative
gene therapies.