Martina Rossi Science Reviews - Biology, 2023, 4(3), 15-18

Acknowledging the Approval of World-First Gene

Therapy for Sickle Cell Disease Through CRISPR-

Mediated Gene Editing

Vertex Pharmaceuticals Incorporated and the Swiss–American biotechnology

company CRISPR Therapeutics, co-funded by the Nobel Prize winner Prof.

Emmanuelle Charpentier.

CASGEVY (exagamglogene autotemcel) is a one-time treatment cell-based gene

therapy. It is intended for the cure of (i) sickle cell disease in patients aged 12 years

and older with recurrent vaso-occlusive crises (VOCs) or (ii) transfusion-dependent β-

thalassemia in patients that are eligible for hematopoietic stem cell (HSC)

transplantation but lack a suitable human leukocyte antigen-matched related donor

for transplantation (1).

problematic as it reduces their flexibility, making them more prone to getting stuck in

small blood vessels, leading to pain and other complications (2). On the other hand, in

β-thalassemia, the HBB gene mutation results in reduced or absent production of β-

globin subunit. This leads to an imbalance in the production of α- and β-globin chains,

causing abnormal haemoglobin formation. The insufficient or absent β-globin chains

hinder the proper function of haemoglobin, leading to ineffective oxygen transport

and, consequently, anaemia (3).

Prior to the development of CASGEVY, the only available treatments for these

conditions consisted of transplanting healthy HSCs from a donor to the patient.

Martina Rossi Science Reviews - Biology, 2023, 4(3), 15-18

haemoglobin (HbF). During fetal development, humans produce a distinct form of

haemoglobin that is more adept at extracting oxygen from the mother's blood across

the placenta. Fetal haemoglobin differs from adult haemoglobin by featuring two γ-

globin subunits in place of β-globin subunits. Ordinarily, the gene associated with the

production of γ-globin is switched off shortly after birth, and the production of adult

haemoglobin takes precedence (5). This is why babies with sickle cell disease and

thalassaemia are born healthy.

CASGEVY utilises CRISPR-based genome editing to selectively "knock out" the

regulator that inhibits blood stem cells from producing HbF (6). More specifically, this

HbF, are then reintroduced back into the patient, who, in turn, undergoes a recovery

period lasting several weeks in the hospital, allowing the cells time to settle back into

the bone marrow. This approach has a distinct advantage over other gene therapies,

as it introduces a smaller genetic change compared to the more classical practice of

inserting an entire working copy of a gene into the cell's genome. Also, CASGEVY

represents a safer and more targeted approach to cure these conditions, marking a

transformative step forward in the quest for effective and treatments for these genetic

disorders.

This groundbreaking achievement, marked by the Medicines and Healthcare products

both sickle-cell disease and transfusion-dependent β-thalassemia. Moreover, while the

safety profile of CASGEVY is highlighted, it is encouraging to see that the MHRA and

the manufacturer are diligently monitoring potential side effects and releasing further

results.

Despite the groundbreaking achievement, the potential global impact of CASGEVY

raises essential considerations about accessibility. Vertex announced pricing

CASGEVY at $2.2 million in the United States. The common thread linking all gene

therapies is the high associated cost stemming from the elevated manufacturing

expenses inherent in personalised medicine. This limitation poses a challenge when

Martina Rossi Science Reviews - Biology, 2023, 4(3), 15-18

treatments, though not unexpected, underscores the need for continued efforts to

make these therapies more accessible on a global scale. Indeed, as we witnessed the

cost of sequencing the whole genome dropping from $2.7 billion to $300 in less than

20 years, we can certainly hope that advancements in CRISPR-based gene therapy may

lead to a decline in the cost of this treatment too.

Overall, the approval of CASGEVY by the MHRA and FDA marks a transformative

milestone in CRISPR–Cas9-mediated gene therapy, demonstrating significant

progress in treating blood disorders. However, the high cost of CASGEVY raises

concerns about global accessibility, emphasising the need for ongoing efforts to reduce