In This Article
- Hematologist Sharl Azar, MD, has devoted much of his career to improving the health and quality of life of patients with sickle cell disease
- Massachusetts General Hospital's Comprehensive Sickle Cell Disease Treatment Center will be an authorized treatment center for the first gene therapeutic for sickle cell disease (SCD)
- In a talk at the Mass General Brigham Gene and Cell Therapy Symposium, Dr. Azar detailed the history of SCD treatments along with the science behind Vertex Pharmaceuticals' Casgevy (exa-cel), the treatment that earned FDA approval for SCD in December 2023
Hematologist Sharl Azar, MD, has devoted much of his career to improving the health and quality of life of patients with sickle cell disease. Now comes news that Massachusetts General Hospital's Comprehensive Sickle Cell Disease Treatment Center, where he serves as medical director, will be an authorized treatment center for the first gene therapeutic for sickle cell disease (SCD).
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In a recent talk at the Mass General Brigham Gene and Cell Therapy Research Symposium, Dr. Azar detailed the history of SCD treatments along with the science behind Vertex Pharmaceuticals' Casgevy (exa-cel), the groundbreaking treatment that earned FDA approval for SCD in December 2023.
Startling Disparities in Race-based Prevalence of SCD
Although SCD is an inherited blood disorder, it touches nearly every organ in the body. The worst complications include stroke, heart attack, osteonecrosis, organ damage, and shorter lifespan. The hallmark of the disease is the sudden, excruciating pain that occurs during vaso-occlusive crises, in which sickle cells get stuck on vessel walls and create blockages that slow or stop the flow of blood and oxygen.
People with SCD have few viable therapeutic options, which is attributable in part to it being "a disease of Black and Brown people," Dr. Azar says. Indeed, SCD is a potent reminder of the inequities that have long plagued the healthcare system. Ninety-eight percent of people with SCD are Black, and rates of SCD are higher among Latinx people and other ethnicities than among white people.
When it comes to SCD, Dr. Azar says, "We are all too used to being last. This is the way our patients have always felt. This is the way that those of us who care for these patients have always felt."
Twenty-Five Years of Stagnation in Developing SCD Treatments
Progress in developing better treatment options for SCD has been frustratingly slow.
In 1998 the FDA approved hydroxyurea for treating adults with SCD. The drug was shown to reduce the rate of vaso-occlusive crises by about half and overall mortality by 40%. Twenty-five years later, hydroxyurea remains the only medication that has been shown to improve mortality in SCD. Unfortunately, new therapies, including several prominent examples from the past several years, have fallen short.
The only potentially curative option for SCD—hematopoietic stem cell transplant—has two significant drawbacks, according to Dr. Azar. First, due to the increase in complications that come with age, the American Society of Hematology (ASH) only recommends allogenic stem cell transplant for patients aged 12 years or younger.
Second, ASH recommends doing the procedure only with a matched sibling donor; patients without one should have the transplant done as part of a clinical trial. But again, the issue of health inequities rears its head: While 70% of white people in the United States will find a donor match through the National Marrow Registry, only 17% of Black people will.
Fetal Hemoglobin Holds the Key
Dr. Azar describes exa-cel as a "transformative therapy" that fulfills a vital task: turning fetal hemoglobin back on.
Fetal hemoglobin typically wanes soon after birth and is gradually replaced by adult hemoglobin. "What drives that is BCL11A, which halts hemoglobin expression naturally within our first year of life and leads us to be able to express beta-globin and ultimately form hemoglobin A [adult hemoglobin] in combination with alpha hemoglobin," Dr. Azar says.
In people with SCD, that adult hemoglobin is hemoglobin S, an inherited variant of normal hemoglobin that leads to symptoms of SCD.
Following the transition in a healthy individual, fetal hemoglobin comprises less than 1% of the total hemoglobin that our red blood cells end up expressing. However, Dr. Azar notes, a subpopulation of patients will continue to produce higher fetal hemoglobin levels throughout their lifetime.
"[This] doesn't have any clinical ramifications in the healthy individual," Dr. Azar says. "But what we have found is that in patients with sickle cell disease who also have hereditary persistence of fetal hemoglobin, the phenotype that they ultimately express is far milder. These patients end up having far fewer vaso-occlusive events and a far lower complication rate overall."
"So reversing gamma-globin expression through BCL11A becomes this very intriguing approach to be able to reverse some of the damaging effects of sickle cell disease."
Therapy Leads to Dramatic Reduction in Vaso-occlusive Events
Administering exa-cel begins with collecting stem cells from the patient and sending them to Vertex. Using CRISPR-Cas9 technology, the stem cells are precisely edited to disrupt the erythroid enhancer region of BCL11A to increase fetal hemoglobin production. Meanwhile, the patient undergoes intensive chemotherapy to prepare their bone marrow for the genetically altered stem cells. Those cells are then returned to the hospital and put back into the patient via a single myeloablative bone marrow transplant.
A study published in 2021 showed exa-cel led to a dramatic reduction in vaso-occlusive events, says Dr. Azar, who adds, "That's why we're so excited about this."
Vertex is partnering with authorized treatment centers (ATCs) to complete the complex, labor-intensive process involved in administering exa-cel. The National Alliance of Sickle Cell Centers and its members established requirements for ATCs, which include having:
- A certified SCD center
- A Foundation for the Accreditation of Cellular Therapy-accredited bone marrow transplant center
- An apheresis unit
- Social work, mental health care, nursing care, and nutritional support services
Following gene therapy completion, patients will return to their home institutions for follow-up care.
Working to Overcome Key Barriers to Administering Exa-cel
Mass General's Comprehensive Sickle Cell Disease Treatment Center is already working to overcome key barriers to administering exa-cel, such as housing for patients traveling long distances for treatment, fertility preservation, and survivorship. Dr. Azar looks forward to this next chapter in SCD care, even though it represents a step into the unknown.
"We find ourselves having to build out protocols that have never been built up before and laying down pathways that have never been laid down before," he says. "Introducing and discussing the modification of genes with patients that have rightfully been skeptical of the healthcare system has been a challenge, and no one is providing us with a script to be able to do that."
"We are attempting to walk the camel through the eye of the needle. It's something we have tried to do for decades in sickle cell disease. We feel ready to be able to do it. We're cautiously optimistic."
The Vertex Foundation made a $2 million gift to support the Comprehensive Sickle Cell Disease Treatment Center in 2022.
Learn about the Comprehensive Sickle Cell Disease Treatment Center
Learn about the Gene and Cell Therapy Institute (GCTI) at Mass General Brigham