A Brutal Disease May Soon Be Transformed

The sickle cell crises were always different. Sometimes Lynndrick Holmes would wake up with a searing pain in his legs, as though there were knives growing out of his bones. Sometimes it was in his arms, like needles digging into his nerves. Other times it was in his chest. The air felt heavy and every breath burned as though there were a barbed wire cage around his lungs.

With each crisis, Mr. Holmes found himself farther away from the future he imagined. He would not serve his country as a Marine. He would not become a writer on a ranch, living a quiet, secluded life. He could not finish community college. He could not even keep a job washing dishes.

By his mid-20s, Mr. Holmes thought about what was ahead for him — sickle cell emergency after emergency, begging for help in Alabama hospitals that saw a Black man and assumed him to be a drug addict — and he started to think about ending his life. “Every time I tried anything, the disease would come and knock me away,” he remembered. “You get tired. You get worn out.”

But in a moment of desperation, he remembered a conversation from his childhood. More than a decade earlier, a nurse told his mother something about stem cells, about the fact that they might cure her boy’s disease one day. Mr. Holmes did not have a doctor whom he trusted. So he went to the library, searched online and soon came upon a trial of gene therapy for sickle cell disease. He sent off an email to the study coordinators at the National Institutes of Health, which he had never heard of. When they replied, he told me, he was so jubilant that “it might as well have been Beyoncé.” There was now hope where there had been none.

In many ways, sickle cell disease encapsulates how the U.S. health care system has failed people like Mr. Holmes. Though there are 100,000 people with sickle cell in the United States and more than 20 million the world over — the vast majority of whom are Black — there has been relatively little funding or scientific advances for this medically and socially complex illness. But now that could change.

The Food and Drug Administration is gearing up to review what could be the first approved gene therapies for sickle cell disease — treatments that could offer functional cures and transform what it means to have this diagnosis. An advisory committee for the agency is meeting to discuss one of the drugs on Oct. 31, with a formal decision by the F.D.A. expected by early December.

This is tremendously exciting. At the same time, there are real concerns about affordability and access to what is a risky and aggressive treatment. There are also complicated questions about how identity shifts when such an all-consuming disease is “cured.” The expected approval of this treatment itself will not erase structural racism or undo decades of medical neglect, of course. But it is a start. The story of gene therapy for sickle cell begins here. This is medicine’s chance to do it right.

Lynndrick Holmes has connected with others suffering from sickle cell disease, to offer education and encouragement.Credit…Ariana Gomez for The New York Times

The genetics behind sickle cell — a disorder in which misshapen, or “sickled,” red blood cells become stuck in blood vessels, leading to excruciating pain, organ failure and early death — were first described in the 1950s. But this understanding has been slow to translate into effective treatment. Today, a life with the disease is often punctuated by hospital admissions for pain crises requiring high doses of opiate medications and the cascading health consequences of frequent blood transfusions. Long term, some patients suffer from strokes and kidney failure and, on average, die two decades earlier than the general population.

And though comprehensive sickle cell care — at dedicated centers with expert hematologists, social workers and pain management specialists — reduces hospitalizations, and is the standard for diseases like cystic fibrosis and hemophilia, which do not disproportionately affect Black people, these centers are few and far between for sickle cell. In many parts of the country, doctors who have no specific expertise in the complexity of the disease manage these patients. Perhaps as a result, even the mainstay of treatment (a medication called hydroxyurea that has been proved to decrease pain crises) is vastly underutilized, with estimates that only around half of those who are eligible are actually on the drug.

Into this complicated landscape enters the possibility of gene therapy. It’s important to note that this isn’t the first cure for sickle cell. A curative option does already exist: bone marrow transplant. Essentially, this means using chemotherapy to wipe out the patient’s existing bone marrow, and with it the unhealthy stem cells that form the sickled blood cells, and replacing it with the healthy marrow of a matched, related donor. This treatment has a high cure rate, but it is risky, burdensome and relies on finding a donor, which can be impossible for many.

Gene therapy works in much the same way but obviates the need for a donor because it uses the patient’s own stem cells. There are many gene therapy products in development. The product that the F.D.A. will first consider in December is called exa-cel and is made by Vertex Pharmaceuticals and CRISPR Therapeutics. It uses CRISPR, a gene editing technology, to turn on the production of a healthy hemoglobin that we all make until shortly after birth. The patients then receive their own edited cells back as an infusion and begin to make red blood cells that do not sickle. Later in December, the F.D.A. is expected to review another gene therapy from the company Bluebird Bio that targets sickle cell disease but does not use CRISPR; this was the therapy Mr. Holmes received as part of the N.I.H. trial.

Patients still need to undergo intensive chemotherapy to prepare their bodies to receive the new cells and face all the attendant risks of wiping out their immune systems, the challenge of fertility preservation beforehand and more. But when they make it through, they can re-enter life freed from pain crises. Whether this effect is permanent remains unknown, but the longest patient in the trial has been followed for more than three years and is without sickle-related health emergencies.

Still, as with bone marrow transplants, there is a delicate balance. Someone needs to be sick enough so that the risk is worthwhile, but not so sick that it is too late. For some, that scale will never tip in favor of a risky treatment. Elizabeth Ford, at 20 years old, lives with constant pain. When she was 17 and hospitalized, facing the reality of her chronic illness, she told her mother that she was ready to pursue gene therapy. She felt as though she had nothing left to lose. Her mother called hospitals around the country with ongoing gene therapy trials, and a few years later, Ms. Ford learned that there was a trial with an open spot.

By this time, she had started college. She dreamed of becoming a doctor. The idea of living without pain was beyond the realm of her imagination, and the cost of pursuing that goal began to feel too high. She knew her pain. She could deal with it. “I really had to think: If I go through this chemo and I pass away because I catch the flu, am I going to be OK leaving my loved ones behind?” When offered the chance, Ms. Ford said no.

But for Mr. Holmes, there was no question. At the N.I.H., he was examined by doctors who treated him with care for what might have been the first time in his adult life. His depression lifted and in its place he found a “deep fight.” He never regretted his decision to enroll in the gene therapy trial, not even in the darkest days, when mouth sores from chemotherapy made him spit up blood and mucus and he could not sleep.

“There was no going back for me. I had a renewed vigor,” he told me. “If sickle cell was going to take my life, it was going to take it inch by inch. I wasn’t going to give it willingly.”

The Food and Drug Administration will soon review two gene therapies for sickle cell disease, including one that Mr. Holmes underwent.Credit…Ariana Gomez for The New York Times

If Vertex’s gene therapy is approved, it will be the first treatment using CRISPR technology to reach the market. Butthe science is just the beginning; true success here relies on dissemination and implementation. If gene therapy is approved, how will our health care system make sure that all patients are educated about their options? When a much simpler drug like hydroxyurea remains underutilized, this is a real challenge. How will we make sure that those like Ms. Ford are given enough information to make a thoughtful decision and are not led one way or another by a medical establishment that has not earned their trust?

Ultimately, the goal is for this therapy to become simpler, for the principles behind the treatment to be applied to a gene editing method that does not require toxic chemotherapy and a month or more in the hospital. While gene therapy will be undertaken by a minority of the sickle cell population, at least initially, these questions will only become more pressing over time.

As will questions of cost. Looking to recently approved gene therapies for comparison, the treatment could carry a price tag of $1 million or more per person. And if this high-cost treatment and necessary chemotherapy and hospitalization are not covered by Medicaid, then this tremendous scientific advance will only accentuate disparities in a disease where disparities are already too prevalent. Finally, for those who do undergo gene therapy, will the worlds that they re-enter acknowledge the complexity of what it means to be cured? Those who have suffered from sickle cell for years often become accustomed to hefty doses of opiates. Their interactions with the medical system are defined by pain and, for so many, by not being believed. Those experiences will continue to reverberate.

“Some of the people who are going for gene therapy have been so tremendously affected by sickle cell that basically their whole lives were about being sick,” said Dr. Lewis Hsu, the chief medical officer at the Sickle Cell Disease Association of America and the director of the pediatric sickle cell program at the University of Illinois at Chicago. “You’re an adult but you’ve never applied for a job. Other people don’t have friends outside their sickle cell peer group,” he continued, extrapolating from the experiences of those who have undergone bone marrow transplants. “Some people almost need a society re-entry program. And then there are others who have blossomed, gone off and done wonderful things.”

When Mr. Holmes returned to his home in Mobile, Ala., after about 90 days of hospitalization at the N.I.H., he found himself with an energy he had never experienced before, a feeling he describes as the “newness of life.” Though he expected those in his world to be elated by his newfound health, it was not that simple. His wife, accustomed to her role as the caretaker, was unable to adjust to the shift and they ultimately divorced. The adjustment was hard on Mr. Holmes, too. He realized that he had come to terms with the idea that he would die young, but living with the knowledge of all his missed opportunities was almost harder. No one had prepared him for that.

But he carried on. He connected with others suffering from sickle cell disease in Alabama, to offer education and to encourage them to keep fighting the disease and advocating for themselves, to move cities to find good care if they had to. Though he would not be able to fulfill his long-held goal of serving as a Marine, he could keep a job, and found work in the county jail as a corrections officer. It was “traumatizing” work at first, but work he is good at and for which he is respected. He writes poetry when he has time. And more recently, Mr. Holmes moved out of Alabama to Austin, Texas.

Now, years after the trial, Mr. Holmes still feels a dull pain in his hip where the bone died because of repeated sickle cell crises. That will not go away. When his legs ache after a good workout he is afraid, for just a moment, that it’s a crisis coming back. But it is not. He is healthy. He does push-ups, runs for miles. Life stretches out ahead of him, and though the days are long, commuting from his home to the jail, and he is still working through his regrets, he has a future. “I feel like I got a lot to catch up on,” Mr. Holmes said. “But it’s better to be behind than to have never been able to play the game at all.”

Daniela J. Lamas (@danielalamasmd), a contributing Opinion writer, is a pulmonary and critical-care physician at Brigham and Women’s Hospital in Boston.

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