How does casgevy gene therapy work? A new chapter for CRISPR technology

October 6, 2025 •

4 min read

In a landmark decision in late 2023, the U.S. FDA approved Casgevy, the first treatment utilizing CRISPR technology to receive authorization. Understanding how does casgevy gene therapy work involves a look at its process of gene editing to enable a patient's body to produce healthy blood cells.

Quick Summary

Casgevy uses the precise CRISPR/Cas9 gene-editing tool to modify a patient's own blood stem cells outside the body, reactivating fetal hemoglobin production to treat sickle cell disease and beta thalassemia.

Key Points

CRISPR/Cas9 Technology: Casgevy is the first FDA-approved therapy using the gene-editing tool CRISPR/Cas9, which acts as molecular scissors to make precise changes to DNA.
Targeting BCL11A: The therapy works by editing the BCL11A gene in a patient's stem cells, which normally suppresses fetal hemoglobin (HbF) production after birth.
Reactivating Fetal Hemoglobin: By disrupting the BCL11A gene, Casgevy enables the body to produce high levels of healthy HbF, mitigating the effects of mutated adult hemoglobin.
Autologous and Ex Vivo: The process is autologous (using the patient's own cells) and occurs ex vivo (outside the body), reducing the risk of immune rejection.
Intense Treatment Process: The full treatment involves stem cell collection via apheresis, lab editing, preparatory chemotherapy to clear the bone marrow, and re-infusion, with a recovery period in the hospital.
Potential for Curative Effect: Clinical trials have shown that Casgevy can eliminate severe pain crises in most SCD patients and achieve transfusion independence in most TDT patients, offering a potentially life-changing or curative effect.

The Mechanism of Casgevy: Reprogramming Blood Cells

Casgevy, also known as exagamglogene autotemcel, represents a paradigm shift in the treatment of genetic blood disorders like sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). Instead of managing symptoms, this one-time gene therapy targets the underlying genetic cause by leveraging the power of CRISPR/Cas9 technology. At its core, Casgevy works by enabling the body to produce high levels of fetal hemoglobin (HbF), a healthy form of oxygen-carrying hemoglobin naturally produced during fetal development.

Reactivating Fetal Hemoglobin

To understand the mechanism, it's crucial to know about the two main types of hemoglobin. Fetal hemoglobin (HbF) carries oxygen efficiently during pregnancy, but its production is typically turned off shortly after birth. Adult hemoglobin (HbA) then takes over. In individuals with SCD and TDT, a genetic mutation causes a problem with adult hemoglobin production.

Casgevy's genius lies in mimicking a naturally occurring benign genetic mutation that causes 'hereditary persistence of fetal hemoglobin' (HPFH). This is achieved by targeting a specific gene called BCL11A, which acts as a molecular 'brake' on HbF production. By editing and disabling the BCL11A gene's activity in the patient's own stem cells, Casgevy allows the body to restart and maintain high levels of HbF into adulthood. This continuous production of healthy HbF counteracts the effects of the faulty adult hemoglobin.

The CRISPR/Cas9 System

CRISPR/Cas9 is a highly precise gene-editing tool that acts like a set of molecular scissors. For Casgevy, the process unfolds as follows:

Guide RNA: A single guide RNA molecule is designed to specifically target the DNA sequence within the BCL11A gene that regulates its expression.
Cas9 Enzyme: The guide RNA leads the Cas9 enzyme to the precise target location within the DNA.
DNA Cut: The Cas9 enzyme makes a precise cut in the DNA strand at the designated site.
Natural Repair: The cell's natural repair mechanisms fix the cut, but in doing so, they disrupt the normal function of the BCL11A gene's erythroid-specific enhancer region. This intentional disruption is what permanently silences the gene.

The Casgevy Treatment Journey

The administration of Casgevy is a complex process that takes place over several months and involves multiple hospital visits. It is a one-time treatment tailored to each patient.

Step 1: Cell Collection

First, a patient receives medication to mobilize or move blood-forming hematopoietic stem cells (HSCs) from the bone marrow into the bloodstream. These cells are then collected through a procedure called apheresis.

Step 2: Gene Editing (Ex Vivo)

The collected stem cells are sent to a specialized lab. There, the CRISPR/Cas9 technology is used ex vivo (outside the body) to edit the BCL11A gene. This process can take several months, during which the patient is typically able to return home.

Step 3: Myeloablative Conditioning

Once the gene-edited cells are ready, the patient is admitted to the hospital for several weeks. They undergo a myeloablative conditioning regimen using chemotherapy to clear out the existing stem cells in the bone marrow, making space for the new, edited cells.

Step 4: Infusion and Engraftment

Finally, the Casgevy product—containing the patient's own CRISPR-edited stem cells—is infused back into their body intravenously. The infused cells then travel to the bone marrow, where they engraft and begin producing red blood cells with increased levels of fetal hemoglobin. Patients remain in the hospital while their immune system recovers and their blood cell counts increase.

Casgevy vs. Lyfgenia: A Comparison

Both Casgevy and Lyfgenia are gene therapies approved for sickle cell disease, but they employ different mechanisms.


Feature	Casgevy (Exagamglogene Autotemcel)	Lyfgenia (Lovotibeglogene Autotemcel)
Mechanism	Uses CRISPR/Cas9 to edit a patient's own hematopoietic stem cells ex vivo.	Uses a lentiviral vector to insert a functional hemoglobin gene into a patient's own stem cells ex vivo.
Gene Target	Downregulates the BCL11A gene to switch fetal hemoglobin production back on.	Inserts an anti-sickling variant of the hemoglobin gene directly.
Effect	High levels of fetal hemoglobin counteract the effects of the faulty adult hemoglobin.	The newly inserted, functional hemoglobin gene suppresses sickling.
Underlying Change	An intentional disruption of a regulatory gene.	The addition of a new, functional gene.
Regulatory Approval	First FDA-approved CRISPR therapy.	FDA-approved lentiviral gene therapy.

Challenges and Long-Term Outlook

Despite its revolutionary approach, Casgevy is not without its challenges. The preparatory chemotherapy is intense, with potential side effects such as painful mouth sores, nausea, hair loss, and impacts on fertility. Because patients are immunocompromised during this phase, a lengthy hospital stay in sterile conditions is required. As with any new therapy, potential long-term side effects, including the risk of off-target gene editing, continue to be monitored through long-term follow-up studies. However, the initial results from clinical trials have been extremely promising, with many patients achieving freedom from vaso-occlusive crises in SCD or transfusion independence in TDT. The development of Casgevy represents a monumental step forward, bringing hope for potentially curative treatments for once-untreatable genetic disorders. More information on clinical trials can be found on the National Institutes of Health website.

Conclusion

Casgevy is a medical milestone, utilizing the precision of CRISPR/Cas9 technology to re-engineer a patient's own blood stem cells. By targeting and disrupting the gene that represses fetal hemoglobin, the therapy effectively reactivates the production of healthy, oxygen-carrying red blood cells, addressing the root cause of sickle cell disease and beta thalassemia. While the treatment process is lengthy and challenging due to the required chemotherapy, it offers a transformative, potentially curative option for eligible patients. The success of Casgevy paves the way for future gene-editing therapies, showcasing the immense potential of CRISPR to rewrite genetic narratives and change lives.

Frequently Asked Questions

Casgevy uses the CRISPR/Cas9 system to edit a patient's own hematopoietic (blood) stem cells. It specifically targets and disrupts the BCL11A gene, which is responsible for turning off fetal hemoglobin (HbF) production after birth. By disabling this 'brake,' the therapy causes the patient's red blood cells to produce high levels of healthy HbF, counteracting the effects of faulty adult hemoglobin.

Yes, Casgevy is designed as a one-time infusion. However, the entire treatment journey, which includes preparing for stem cell collection, the editing process, chemotherapy, and recovery, can take up to a year to complete.

While the clinical trials are ongoing, Casgevy offers a potentially transformative therapy. For sickle cell disease, it has shown the ability to eliminate or greatly reduce severe pain crises. For beta thalassemia, it enables most patients to become transfusion independent. The results are considered life-changing, but whether it is a complete and technical 'cure' is still being assessed.

The process involves several key steps: mobilizing and collecting a patient's blood stem cells, sending the cells to a lab for CRISPR/Cas9 gene editing, undergoing myeloablative chemotherapy to clear existing bone marrow cells, receiving the one-time Casgevy infusion, and a hospital recovery period.

The most common side effects are related to the conditioning chemotherapy required before the infusion. These can include low levels of blood cells (leading to infection risk and bleeding), painful mouth sores (mucositis), nausea, vomiting, and fatigue. Fertility may also be affected.

Both are gene therapies for sickle cell disease, but their mechanisms differ significantly. Casgevy uses CRISPR/Cas9 to switch on fetal hemoglobin production. In contrast, Lyfgenia uses a lentiviral vector to insert a new, functional hemoglobin gene into the stem cells.

With any gene-editing approach, there is a theoretical risk of unintended or 'off-target' edits. However, Casgevy uses a highly precise CRISPR/Cas9 system, and clinical trials have not reported off-target effects. Long-term monitoring will continue to assess this potential risk.