Are We About to Cure Sickle-Cell Disease?

Via Peters

In September, 1904, a twenty-year-old Grenadian man named Walter Clement Noel disembarked in New York after an eight-day voyage from Barbados. At the time, few Black people were permitted to study at most American universities, but Noel—who was well off, well educated, and a foreigner—had secured a spot at the Chicago College of Dental Surgery. During his journey, he’d developed a painful sore on his ankle; after clearing customs and immigration, he sought out a doctor, who applied a tincture of iodine to the wound. The ulcer healed, leaving a scar similar to others on his body. Noel headed to dental school. But, by Thanksgiving, he’d developed a cough and serious trouble breathing. He felt weak, dizzy, and feverish. A few weeks later, he stumbled into a hospital, where a medical resident named Ernest Irons studied Noel’s blood under a microscope.

The findings were so unusual that Irons immediately alerted his supervising physician, James Herrick. Red blood cells normally look like smooth disks—tiny saucers, concave on both sides, that shuttle oxygen around the body. But Noel’s blood, Herrick later wrote, had a “large number of thin, elongated, sickle-shaped and crescent-shaped forms.” For the next two and a half years, Herrick and Irons followed Noel as he pursued his dental studies and suffered through joint problems, gastrointestinal upset, difficulty breathing, and episodes of severe pain. They failed to arrive at an explanation for his condition—or at a treatment for it.

Noel returned to Grenada, where he practiced dentistry until he died of pneumonia, at the age of thirty-two. Meanwhile, other American doctors read Herrick’s report of the disease and found patients of their own. By the nineteen-twenties, doctors were recognizing sickle-cell disease as a distinct, hereditary form of anemia, and its varied manifestations had been well described by physicians and researchers. In 1949, the eminent biochemist Linus Pauling published a paper linking the illness to hemoglobin, an oxygen-carrying protein in the blood. Among sufferers, the structure was abnormal. Pauling described sickle-cell as a “molecular disease.” This raised a tantalizing possibility: find a way to fix the broken molecule, and you’d have a cure.

Such a cure was a long way off. Molecular biology was in its infancy. And, in the decades following, sickle-cell disease would be under-studied, in large part because in America it mostly affects individuals of African descent. It sickens nearly three times as many people as cystic fibrosis, but, until recently, research into sickle-cell disease received a tenth of the funding per patient; the 2014 Ice Bucket Challenge for amyotrophic lateral sclerosis (A.L.S.), or Lou Gehrig’s disease, raised a hundred times as much money as sickle-cell research received from philanthropic foundations around the same time.

Sickle-cell disease afflicts some hundred thousand Americans; the C.D.C. estimates that one in every three hundred and sixty-five Black babies is born with the condition. Those with severe cases have a life expectancy of about forty-five years. Only a handful of sickle-cell medications have been approved by the F.D.A., and many patients struggle to access medical care and report biased treatment when they do. In my clinical practice, I often care for sickle-cell patients hospitalized with excruciating pain—a stabbing, throbbing agony that tears through their legs, backs, ribs, and chests. A so-called sickle-cell crisis might be precipitated by infection, dehydration, stress, a change in seasons, or nothing at all; somebody in the midst of one might require blood transfusions and high doses of opioid medications. Not infrequently, by age twenty or thirty, my patients have suffered strokes and been started on dialysis, or have had their hips replaced and spleens removed. Many are in and out of the hospital every few months; some, every couple of weeks.

Very soon, all this could change. More than a century after sickle-cell disease was first diagnosed, advances in gene therapy are poised to make it not just treatable but curable. But technology is only one part of medicine. The treatments won’t be cheap, and many of the people who need them the most are on the fringes of a medical system that has marginalized them. Sickle-cell disease traces the deep, long-standing inequities of American society. Defeating it will require confronting them.

Hemoglobin, a tiny, four-part protein, is used by our red blood cells to ferry oxygen throughout our bodies. In humans, hemoglobin is initially constructed using two alpha units and two gamma units; during the first few months of life, the body mostly stops producing gamma and starts producing beta, with which alpha then pairs. But a single mutation on chromosome 11 modifies the beta unit. The result is hemoglobin S—a misshapen version that causes red blood cells to sickle. Some people inherit only one copy of this mutated gene; they’re said to have sickle-cell trait, and live more or less normal lives. For those who inherit two copies, the effects can be devastating.

Healthy red blood cells are pliable, and swim easily through the body’s intricate network of vessels. But hemoglobin S congeals into taut strands, making the blood cells that carry it fragile and rigid, as though a balloon were filled with shards of ice. The cells break easily and have trouble clearing tight passageways; they stick to vessel walls, causing traffic jams that stymie on-time oxygen delivery. Whereas healthy red blood cells live for three or four months, sickle cells die within weeks. Our bone marrow, which makes our blood cells, works feverishly to churn out replacements but can’t keep up. Patients suffer from fatigue, acute pain, and everything in between.

If the sickling gene is so harmful, why do roughly one in every thirteen Black Americans carry it? In the early nineteen-fifties, Anthony C. Allison, a geneticist, discovered that the sickle-cell trait confers protection against malaria. When the parasite that causes malaria infects the red blood cells of someone who possesses the trait, it has trouble hijacking the replication machinery. The sickling gene appears to be most prevalent in regions where malaria is endemic, particularly in southern Europe and Africa; nearly eighty per cent of sickle-cell births occur in sub-Saharan Africa. It’s a Pyrrhic victory—a mutation that protects against one disease by risking another.

In 1998, the F.D.A. approved hydroxyurea, a cancer drug, for the treatment of sickle-cell disease. For reasons that are still not fully understood, the medication ramps up production of fetal hemoglobin—the alpha-gamma version of the protein that’s present right after birth. Fetal hemoglobin acts like normal adult hemoglobin, and the drug decreases the proportion of sickled hemoglobin in the bloodstream, reducing the frequency of painful sickling events. But it also has numerous side effects and doesn’t work for everyone; many patients I see in the hospital have been on it for years. Since 2017, three more medications have been approved for sickle-cell disease: the amino acid L-glutamine; voxelotor, a hemoglobin-stabilizing drug; and a monoclonal antibody known as crizanlizumab. Each has some benefits but is far from a cure; the latter two can cost a hundred thousand dollars a year.

For decades, bone-marrow transplants have offered a potentially curative option for patients with sickle cell. But the process is risky and harrowing. First, high doses of chemotherapy must be used to wipe out most of a patient’s existing bone-marrow cells; then healthy donor stem cells are transplanted into the bone marrow, where they can produce properly shaped hemoglobin. But transplant patients are at high risk of infection throughout the process. And although the healthy stem cells are most often taken from a close relative, fewer than one in five sickle-cell patients has a sibling who is an eligible match. Many face some level of transplant rejection, and all must take powerful immunosuppressive medications afterward. Only about twelve hundred such procedures have been performed in the U.S. since 1984.

In 2019, Haydar Frangoul, a pediatric hematologist at the Sarah Cannon Research Institute, in Nashville, became the first clinician to try a new twist on the transplant technique: as part of a clinical trial, he extracted a patient’s own bone-marrow cells from her blood, edited their DNA using the gene-editing technology CRISPR, and then reintroduced them. The cells had been modified so that they produced fetal hemoglobin; because they were the patient’s own, she didn’t need a donor and there was little risk of rejection. The patient, a thirty-three-year-old woman named Victoria Gray, had suffered from crushing fatigue and attacks of debilitating pain since childhood. These episodes worsened during her twenties, and she was prescribed a cocktail of powerful pain medications, including fentanyl and oxycodone. Even so, every few months, she would be hospitalized with unbearable pain; every few weeks, she needed a blood transfusion. “I was tired and depressed,” Gray told me. “I felt like I wasn’t living—I was barely existing.” Gray, who has four children, spent most of her time in bed; she needed help getting in and out of the bathtub. She spoke with her hematologist about the possibility of a bone-marrow transplant. “I told her, ‘Look, something has to be done,’ ” Gray recalled. “I’m getting to the point where I’m ready to give up. I can’t keep doing this.”

Gray struggled to find a suitable donor. Her brother was a partial match; despite the elevated risk of rejection, they travelled to Nashville to proceed with a transplant. On one of these trips, Frangoul approached her about the CRISPR trial. I asked her why she decided to pursue an experimental treatment. “When you feel like you’re out of options, anything is worth a try,” she said.

After the therapy, Gray felt as though she’d been cured. She hasn’t been hospitalized in more than two years and needs no pain medications. “I don’t feel like I have sickle cell at all,” she said. “I work full time. I enjoy my kids. I don’t have to worry that I’m going to end up in the emergency room when the weather changes. I’m not tired and drowsy from taking all these narcotics.” She went on, “I can make plans—just regular plans, to go on vacation, to do things with my kids—without fear that I will bring everyone down by starting off with a good day but then start hurting and have a crisis.” Gray began to tear up, and her voice cracked. “I can do all the things I always wished and dreamed that I could one day do,” she said.

https://www.newyorker.com/science/annals-of-medicine/are-we-about-to-cure-sickle-cell-disease

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