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
Dear Editor,
Emerging as a cutting-edge technology, CRISPR has garnered a lot of attention for its
potential in addressing various genetic diseases over the past decade. Recently, this
promise has materialised with the groundbreaking approval of CASGEVY, a CRISPR-
based gene therapy co-developed by the American biopharmaceutical company
Vertex Pharmaceuticals Incorporated and the SwissAmerican 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).
Sickle cell disease and β-thalassaemia originate from genetic mutations within the HBB
gene, responsible for encoding the β-globin subunit of haemoglobin A (HbA), the
primary oxygen-carrying protein in adult red blood cells (RBCs). In individuals with
sickle cell disease, the HBB mutation causes the production of abnormal haemoglobin
molecules, known as haemoglobin S (HbS). The sickle shape of these cells is
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.
However, such a procedure is associated with substantial risks, including the potential
for life-threatening graft-versus-host disease. Also, only about 10% of patients affected
by the disease have a histocompatible sibling donor, making the cure inaccessible to
the majority of those affected (4).
Martina Rossi Science Reviews - Biology, 2023, 4(3), 15-18
CASGEVY capitalises on a unique aspect of human biology related to fetal
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
cell-based gene therapy involves collecting autologous CD34+ HSCs. These cells then
undergo CRISPR-Cas9-mediated gene editing to silence the expression of the BCL11A
gene, a crucial regulator of the gene encoding the γ-globin subunit in adulthood (5).
Specifically, the editing occurs at the erythroid-specific enhancer region of the BCL11A
gene. Once ready, patients undergo a few days of chemotherapy to eliminate the old
cells and create space for the modified ones. The edited cells, now capable of producing
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
Regulatory Agency (MHRA) in the UK and subsequently approved by the U.S. Food
and Drug Administration (FDA) earlier this month, signifies a remarkable milestone
in the field of CRISPRCas9-mediated gene therapy (1, 6). The approval by the MHRA
and the FDA represents a significant leap forward in the treatment landscape for these
debilitating blood conditions. To this date, CASGEVY is currently under review by the
European Medicines Agency (EMA) and the Saudi Food and Drug Agency (SFDA) for
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
delivering this therapy to low- and middle-income countries. The high cost of such
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 CRISPRCas9-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
expenses and make such revolutionary therapies more widely available.
Thank you for your dedication to disseminating this critical groundbreaking scientific
advancement.
Sincerely,
Martina Rossi
*
, PhD
*
Independent Researcher, Strasbourg, France; martina.rossi108@gmail.com
https://orcid.org/0000-0002-8866-1844
https://doi.org/10.57098/SciRevs.Biology.2.4.3
References
1. Pflaum, C. (2023). FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease”.
FDA News Release, 8 December. Available at: https://www.fda.gov/news-events/press-
announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
2. Rossi, M. (2023). Advancements and Challenges in Gene Therapy Approaches for Sickle Cell
Disease: A Comprehensive Review”, SciRevs Biology, 2(3), p. 3.
https://doi.org/10.57098/SciRevs.Biology.2.3.3.
3. Thein, S. L. (2017). Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease,
Adv. Exp. Med. Biol. https://doi.org/10.1007/978-1-4939-7299-9_2. PMID:29127676.
4. Germino-Watnick, P., Hinds, M., Le, A., Chu, R., Liu, X., & Uchida, N. (2022). Hematopoietic Stem
Cell Gene-Addition/Editing Therapy in Sickle Cell Disease”, Cells, 11(11), 1843.
https://doi.org/10.3390/cells11111843. PMCID: PMC9180595. PMID: 35681538.
5. Sankaran, V. G., & Orkin, S. H. (2013). The Switch from Fetal to Adult Haemoglobin, Cold Spring
Harb Perspect Med, 3(1), a011643. https://doi.org/10.1101/cshperspect.a011643. PMCID:
PMC3530042. PMID: 23209159.
6. Wong, C. (2023). UK first to approve CRISPR treatment for diseases: what you need to kno, Nature.
https://doi.org/10.1038/d41586-023-03590-6.