Transformative Gene Therapies Greenlit for Sickle Cell Disease

In sickle cell anemia, red bloods cells elongate into an abnormal “sickled” shape

Sickle cell disease is a debilitating blood disorder that causes recurrent pain crises and severe health effects, and can drastically impact quality of life. Recently, Vertex Pharmaceuticals and CRISPR Therapeutics introduced Casgevy, or exa-cel, a novel form of gene therapy that could radically change the management of sickle cell disease. On the heels of exa-cel’s approval in Britain, this groundbreaking therapy was also recently approved in the U.S.

What is Sickle Cell Disease?

Sickle cell disease is a hereditary type of anemia that stems from mutations in the HBB gene coding for the beta-globin subunit of hemoglobin (HbA), the protein responsible for oxygenating blood. This mutation results in the production of an abnormal form of hemoglobin (HbS) that gives red blood cells an elongated, or sickled, shape, precluding the normal flow of blood and causing small blood vessels to clog. This leads to excruciating pain and complications including organ damage, stroke, pulmonary hypertension, cardiovascular disease and more. Untreated, sickle cell disease can be crippling and can result in premature death. There are limited options for treatment, bone marrow transplant being the only one among these that could be considered potentially curative. Other treatments include a medication called hydroxyurea that increases fetal hemoglobin, blood transfusions and acute pain management. Today, it is estimated that around 100,000 people in the U.S. suffer from sickle cell disease.

Patients with this condition frequently face obstacles to compassionate and comprehensive healthcare, and limited social awareness can often result in feelings of alienation, depression and anxiety. Historical health inequities and racism in the U.S. have shaped the mischaracterization of sickle cell disease as one that exclusively impacts African Americans, leading to a lack of investment in research and infrastructure, further exacerbating the challenges that African Americans already face in seeking quality care. Discrimination also poses issues for pain management when a patient’s pain is not taken seriously and they are labeled as “drug-seeking”, a problem made worse due to the opioid epidemic and the wide adoption of a “one size fits all”, limited approach to pain management.

Even in the unlikely event that a good match is found and a patient is able to procure a bone marrow transplant, the procedure carries the risk of rejection, graft vs. host disease and other complications. Cell-based gene therapy for sickle cell disease has been posited as a targeted solution that could prove more effective than current therapies, and is now possible with the application of the gene-editing tool, CRISPR.

Enter CRISPR Gene Editing

In early December 2023, two gene therapies for sickle cell disease received approval in the United States: Lovotibeglogene autotemcel (lovo-cel) from the biotechnology company bluebird bio and exagamglogene autotemcel (exa-cel) from Vertex Pharmaceuticals and CRISPR Therapeutics.

Lovo-cel uses a lentivirus vector to introduce a functioning form of the HBB gene into a patient’s own stem cells. Exa-cel, on the other hand, uses CRISPR to deactivate BCL11A, a gene responsible for preventing the body from creating fetal hemoglobin (HbF). HbF is present only during fetal development and is more efficiently oxygenated than adult hemoglobin, allowing the fetus to glean oxygen from the mother’s blood through the placenta. Following birth, HbF is replaced with adult hemoglobin (HbA). If there are problems with the gene coding for HbA, as is the case for those with sickle cell disease, reactivating the production of HbF can reduce cell sickling, and thereby mitigate symptoms.

With exa-cel, doctors extract a patient’s bone marrow stem cells, edit them to deactivate BCL11A (facilitating the production of HbF), eliminate the remaining untreated bone marrow and reinfuse the edited cells. Theoretically, the edited cells will then continue to produce HbF indefinitely, providing a treatment that could last a lifetime. In clinical trials, 29 of 30 study participants with sickle cell anemia reported no pain for one year following exa-cel transfusions, and 39 out of 42 with a type of sickle cell disease called beta-thalassemia no longer needed blood transfusions or bone marrow transplants.

Benefits and Drawbacks

Gene therapies like exa-cel and lovo-cel have the potential to be life-changing for patients with sickle cell disease, effectively reducing pain and providing significant improvement in overall quality of life. The treatment has been approved for those 12 and older, which may be crucial to preventing irreversible organ and bone damage early on. However, costs as high as $2 million per patient may be prohibitive for many, possibly preventing un- or underinsured patients from receiving what could be life-saving treatment. The process involved is months-long and grueling, including extensive tests, procedures like chemotherapy treatments and blood transfusions, as well as an invasive bone marrow transplant. There is also uncertainty about unforeseen long-term or off-target effects (unintentional modifications to the genome) which are always a possibility with gene-editing techniques.

Alternative Sickle Cell Therapies

A treatment commonly used for some blood cancers called a haploidentical transplant, or “half-matched” transplant, could be an alternative approach, and involves replacing someone’s bone marrow stem cells with those of a healthy parent or sibling. Many of the countries where sickle cell anemia is most prevalent have insufficient medical infrastructure to support gene therapy treatments, and haploidentical transplant could be a better option in these places. It may also represent a more affordable alternative for those in the U.S. who face financial barriers to gene therapy.  

Hope for the Future

The introduction of novel gene therapies like exa-cel and lovo-cel has revolutionized the treatment of sickle cell disease, providing much-needed hope for those affected by this condition. These therapies promise a significant reduction in symptoms and offer the potential for a better quality of life. Accessibility, cost and the lack of long-term safety data are challenges that will need to be addressed—as physicians, pharmaceutical companies and insurance agencies navigate these issues, it will be important to advocate for comprehensive care, increased awareness and continued funding to ensure that these groundbreaking therapies are accessible and safe for all who need them.


The world’s first gene therapy for sickle cell disease has been approved in Britain | AP News

A new cure for sickle cell disease may be coming. Health advisers will review it next week | AP News

Gene-editing treatment for sickle cell appears headed for FDA approval : Shots – Health News : NPR

FDA Approves First CRISPR Treatment in U.S. | TIME


FDA Approves First CRISPR Gene Editing Treatment for Sickle Cell Disease | Scientific American

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AnnaKay Kruger
AnnaKay is a science writer at Promega. She studied Life Sciences Communication at the University of Wisconsin-Madison and has written across a range of fields including limnology, veterinary medicine and natural resource management. In her spare time, AnnaKay enjoys reading and writing creatively.

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