Feature Story | 2-Jan-2024

BU researchers helped develop the first FDA-approved gene therapies to treat sickle cell disease

Experts explain how groundbreaking CRISPR- and gene therapy–powered treatments work and how they plan to deliver them to more patients

Boston University

For the tens of thousands of people with sickle cell disease, a group of painful inherited blood disorders, there’s new hope for a cure. The US Food and Drug Administration (FDA) has approved two groundbreaking treatments—both developed with the help of Boston University researchers—that alter genes to reduce a mutation in red blood cells. One of the therapies, Casgevy, is the first FDA-approved drug to utilize CRISPR/Cas9, a gene-editing technique discovered in the early 2000s.

“This therapy is highly efficacious,” says Martin Steinberg, a BU Chobanian & Avedisian School of Medicine professor of medicine, who is part of the team that developed Casgevy. “It wasn’t too many years ago that the idea of gene therapy was science fiction.”

Along with Casgevy, the FDA approved another cell-based therapy to treat the disease, called Lyfgenia, developed by Somerville, Mass.–based Bluebird Bio. Jean-Antoine Ribeil, a BU Chobanian & Avedisian School of Medicine associate professor of medicine, was formerly Bluebird’s associate medical director. He’s studied the therapy—which uses a gene-addition technique, rather than gene editing—for over a decade.

Sickle cell disease impacts hemoglobin, the protein in red blood cells that delivers oxygen to every part of the body. Normally, red blood cells are disc shaped, but the disease causes them to be shaped like a crescent or sickle. This leads to a lifetime of medical complications, including blood vessel blockages, infections, severe pain episodes (called vaso-occlusive events), inflammation, fatigue, reduced flow of oxygen to tissues, organ damage, and more. Studies—including Casgevy clinical trials that Steinberg helped run—suggest the newly approved gene-editing and gene-addition treatments can eliminate pain episodes, which are the most common reason for hospitalization, by increasing the normal flow of oxygen throughout the body.

“Even though the genetic mutation affects the hemoglobin molecule within red blood cells, it affects every blood vessel throughout the body,” says Elizabeth Klings, a BU Chobanian & Avedisian School of Medicine professor of medicine and director of BU’s Center of Excellence in Sickle Cell Disease, the largest sickle cell treatment center in New England. The center, located at Boston Medical Center, BU’s primary teaching hospital, will offer both gene therapies to patients. They treat roughly 600 adult and pediatric sickle cell patients annually.

There are about 100,000 people in the US living with sickle cell disease, and an estimated 20 million worldwide. Most people who have the disease in the US are of African ancestry; about 1 in 365 Black Americans are born with sickle cell disease, according to the National Institutes of Health. It’s also more likely in people with Hispanic, Southern European, Middle Eastern, or Asian Indian backgrounds. The only existing cure for sickle cell is a bone marrow transplant that relies on finding a HLA-matched donor—which is impossible for many people. Gene therapy instead alters a person’s own blood stem cells, eliminating the need to find a match.

“For patients, this is transformative,” says Ribeil, clinical director of BU’s Center of Excellence in Sickle Cell Disease, about both therapies. “For the patients that I’ve treated, I see how they’re able to have a normal life—they don’t have emergency hospital visits anymore, they just have regular medical checkups.” 

Revolutionary, Yet Complicated and Costly 

The FDA’s approval announcement says that patients who’ve received Casgevy or Lyfgenia during trials will be followed in a long-term study to evaluate each product’s safety and effectiveness. There are currently four other FDA-approved medications to treat the condition—including one called hydroxyurea, the first FDA-approved drug for sickle cell disease, which Steinberg also helped develop. While they’ve been shown to reduce the frequency of pain episodes, those medications don’t eradicate the episodes like the gene therapies do.

Casgevy, developed by the Boston-based companies Vertex Pharmaceuticals and CRISPR Therapeutics, works by suppressing a gene that inhibits the body’s production of fetal hemoglobin—the type of hemoglobin produced before birth and in the first few weeks of life. For those with the disease, fetal hemoglobin is not misshapen like adult hemoglobin, which is why symptoms don’t begin until about three or four months old. By targeting that specific gene, adult cells are able to start producing fetal hemoglobin, replacing sickle cells. This is done by altering blood-producing stem cells in the lab with CRISPR/Cas9. This gene-editing tool, which won the 2020 Nobel Prize in Chemistry, relies on a guide RNA (gRNA) molecule that directs the Cas9 enzyme to cut the correct region of DNA, disrupting the production of hemoglobin.

After Casgevy is delivered, patients have a new red blood cell population in a matter of weeks, made up of about 40 percent fetal hemoglobin, Steinberg says. “The rest is still sickle hemoglobin, but it turns out 40 percent is enough to stop acute sickle cell events over the years.”

With Lyfgenia, a patient’s blood stem cells are genetically modified by adding a beta-globin gene, one of the four proteins that make up hemoglobin, to produce cells that function similarly to regular adult hemoglobin. It’s added with a process known as lentiviral vector gene addition, a tool used in treatments for other severe illnesses, including cancer and thalassemia.

Both therapies involve obtaining a patient’s stem cells, altering them in the lab, removing bone marrow to make room for new cells, engrafting the altered cells, and giving the patient a blood transfusion. The entire process takes over a month in the hospital, and can cost millions of dollars, making both therapies potentially inaccessible to those on limited health insurance plans. Plus, chronic hospital visits before treatments put people at a financial disadvantage. Given that the disease in the US primarily affects Black and African Americans, communities that are disproportionately impacted by poverty and economic barriers, many patients and experts have raised questions about who will be able to access treatments.

“This is a disease of tremendous healthcare disparities, and clinical care has been impacted significantly by this in many ways,” says Klings. According to Klings, about 80 percent of sickle cell patients at BMC, and nationwide, are covered by Medicare or Medicaid.

Earlier this month, Ribeil penned an article in La Presse Médicale highlighting the need to address the extremely high price tag for any type of gene therapy, pointing out that access to this treatment is limited by the cost, especially in low-resource settings.

“I think all of these gene therapies are unbelievable first steps, but over the next 10 years or so, we’ll see the method refined so there’s a possibility that it will become even more effective,” Steinberg says. He hopes continual evolution of the therapies will make the process less costly and complicated, and help providers better reach the populations who need them.

“Now that gene therapy is approved, it’s going to be crucial that we’re able to provide these therapies for our patients, because that’s the big concern that many have,” Klings says.


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