Amazing Science

At age 45, Dr. Lakiea Bailey said, she was the oldest person with sickle cell anemia that she knew. The executive director of the nonprofit patient advocacy group the Sickle Cell Consortium was diagnosed with sickle cell disease at age 3. Because of it, she’s had heart problems, had her hips replaced, and experienced serious pain all her life. Bailey told the US Food and Drug Administration’s independent advisory committee that she believes a cutting-edge therapy that is currently under review offers the sickle cell community something many haven’t ever had before: hope. “Hope is on the horizon, and we are looking toward this hope for a change of the lives that we are living of excruciating pain,” Bailey told the FDA committee.

The independent committee is helping the FDA think through how it should evaluate a treatment called exa-cel that could potentially cure people of sickle cell disease, a painful and deadly disease with no universally successful treatment. This was an ongoing discussion with no vote or decision about the therapy, but the discussion likely moves the US one step closer to approving a groundbreaking new treatment that uses gene editing. If approved, exa-cel, made by Boston-based Vertex Pharmaceuticals and the Swiss company CRISPR Therapeutics, would be the first FDA-approved treatment that uses genetic modification called CRISPR. CRISPR, or clustered regularly interspaced short palindromic repeats, is a technology researchers use to selectively modify DNA, the carrier of genetic information that the body uses to function and develop. The FDA said treatment for severe sickle cell is an “unmet medical need.”

When someone has sickle cell disease their red blood cells don’t function the way they should. Red blood cells are the helper cells that carry oxygen from the lungs to the body’s tissues, which use this oxygen to produce energy. The process also generates waste in the form of carbon dioxide that the red blood cells take to the lungs to be exhaled out.

With sickle cell disease — also called sickle cell anemia — red blood cells take on a folded or sickle shape that can clog tiny blood vessels and cause progressive organ damage and pain, and can lead to organ failure. The sickle cells also die earlier than they should, which means the person is constantly short red blood cells. One person with sickle cell who testified said she had been hospitalized 100 times just last year. Median life expectancy is only 45 years. Sickle cell is rare, and it disproportionately impacts African Americans. About 100,000 people in the US are diagnosed with sickle cell and, of those, 20,000 have what’s considered severe disease. Up until now, the only real treatment has been a stem cell or bone marrow transplant. For stem cells, fewer than 20% of patients have an appropriately matched donor, the FDA said, and the transplants are risky and may not work. Sometimes a transplant can kill the patient. The new exa-cel treatment under FDA consideration can use the patient’s own stem cells. Doctors would alter them with CRISPR to fix the genetic problems that cause sickle cell, and then the altered stem cells are given back to the patient in a one-time infusion. In company studies, the treatment was considered safe, and it had a “highly positive benefit-risk for patients with severe sickle cell disease,” Dr. Stephanie Krogmeier, vice president for global regulatory affairs with Vertex Pharmaceuticals Incorporated, told the panel. Thirty-nine of the 40 people tested with the treatment did not have a single vaso-occlusive crisis, which means the misshapen red blood cells block normal circulation and can cause moderate to severe pain. It’s the top reason patients with sickle cell go to the emergency room or are hospitalized. Before the treatment, patients experienced about four of these painful crises a year, resulting in about two weeks in the hospital. The FDA sought the independent panel’s advice, in part, because this would be the first time the FDA would approve a treatment that uses CRISPR technology, but Dr. Fyodor Urnov, a professor in the Department of Molecular and Cell Biology at the University of California, Berkeley, reminded the committee CRISPR has been around for 30 years and, in that time, scientists have learned a lot about how to use it safely. “The technology is, in fact, ready for primetime,” Urnov said. With this kind of genetic editing, scientists could inadvertently make a change to a patient’s DNA that is off-target, and the therapy could harm the patient. The FDA wanted the experts’ advice so it could understand what criteria it should use to evaluate the treatment and determine how to evaluate long-term safety issues.

An FDA presentation to the panel suggested the agency may have some questions about the data. It called a lack of confirmatory testing “concerning.” It also noted the study’s small size. In a discussion of the company’s methodology, several panel experts said that they believed the data the companies have submitted for FDA approval were reasonable. Committee member Dr. Gil Wolfe, a distinguished professor in the department of neurology at University at Buffalo Jacobs School of Medicine and Biomedical Sciences, said he liked that the company promised to monitor patients for 15 years to see if there were any problems down the road. He said, generally, it was “exciting” to see how many patients have been treated and how positive the results have been so far. As far as any concern for what’s called “off-target effects,” meaning the potential unwanted or adverse alterations to the genome that could accidentally happen in this process and cause cancer or other problems down the road, Dr. Daniel Bauer, principal investigator and staff physician at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston Children’s Hospital, told the panel the risk is “relatively small.” Wolfe thought the depth of analysis the companies used should be good enough to detect any potential problems down the road. “We want to be careful to not let the perfect be the enemy of the good,” Wolfe said. “At some point, you have to just try things out.” “I think, in this case, that there’s a huge unmet need for individuals with sickle cell disease, and it’s important we think about how we can advance therapies that could potentially help them, and I certainly think this is one of them,” Wolfe added. Asked by the committee how he would advise patients how to evaluate the risks with this treatment, Bauer said he would be honest that there is some uncertainty, but most of the human genome is non-coding, meaning it doesn’t provide instructions to the cells to act a certain way. “It might be that many places in the human genome can tolerate an off-target edit and not have a functional consequence,” Bauer told the committee. In other words, if they made an editing error, it might not matter, and may not harm the patient. “My guess is it’s a relatively small risk in the scheme of this risk benefit. But it’s new, it’s unknown,” Bauer said. “We need to be humble and open to learning from these brave patients participating.” The FDA is expected to make an approval decision by December 8, 2023.

A new study highlights both the promise and the limitations of gene editing, as a highly lethal form of avian influenza continues to spread around the world.