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After decades of neglect, sickle cell disease could soon be transformed with gene-based therapies

Dvaizea Moore and his wife, Julie, relaxed on their front porch after work in Birmingham, Ala. Moore recently underwent treatment for sickle cell disease.Meg McKinney for The Boston Globe

It’s one of the great paradoxes of medicine.

Sickle cell disease was the first human disorder understood on a molecular level, its underpinnings explained in a landmark 1949 paper by a future two-time Nobel laureate.

Yet the inherited blood disease ― which causes unpredictable bouts of crushing pain, damages organs, and cuts lives short ― has eluded transformative treatments longer than a number of other genetic diseases, including far rarer ones. Sickle cell mostly affects people of color, and many experts attribute the slower progress in developing medicines to structural racism, especially in funding for research.

But the outlook for the estimated 100,000 Americans suffering from the condition could improve soon.

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Two rival gene-based treatments developed by three biotech firms with headquarters, or most of their operations, in Massachusetts could be approved late this year or early in 2024.

The medicines ― a gene therapy from Bluebird Bio and a gene-editing treatment by a partnership between Vertex Pharmaceuticals and CRISPR Therapeutics ― have generated extraordinarily promising results in clinical trials. Some scientists even call them “potentially curative,” although others say that conclusion is premature.

Still, no one disputes that the one-time intravenous infusions could mark the biggest scientific advance ever in treating sickle cell disease.

“They’re both amazing,” said Dr. Julie Kanter, director of the adult sickle cell clinic at the University of Alabama at Birmingham and one of the principal investigators for Bluebird’s trial, who says it’s too soon to use the word ‘cure.’ “I call the therapy highly transformative ― both of them.”

Recipients of the experimental treatments report dramatic decreases in the searing pain crises that are a hallmark of sickle cell. The change is so life-altering, some patients say, that they have been able to hold down a job for the first time in years.

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Dr. Haydar Frangoul, medical director of pediatric hematology/oncology at the Sarah Cannon Research Institute in Nashville, with Victoria Gray, first recipient of a sickle cell gene-editing treatment from Vertex Pharmaceuticals and CRISPR Therapeutics, during a visit to the institute in June 2020. Amanda Stults, RN, Sarah Cannon Research Institute/The Children’s Hospital at TriStar Centennial

“If I have pain, it’s from working, which I’ll take any day,” said Victoria Gray, 37, who in 2019 became the first patient to have her genes edited in the Vertex-CRISPR clinical trial and has worked since December 2021 as a cashier at Walmart in Forest, Miss. “I’m still a sickle cell patient, but I don’t have sickle cell occurrences.” Gray underwent treatment at Sarah Cannon Research Institute in Nashville.

Dvaizea Moore, who at 5 years old suffered a stroke brought on by sickle cell disease, reported similar results about the Bluebird gene therapy he received in February at the University of Alabama at the suggestion of his doctor, Kanter.

“I haven’t had any pain since the transplant, and it’s never been like that in my life,” said Moore, 29, who lives near Birmingham and recently began working as a car mechanic.

Despite such remarkable outcomes, several sickle cell specialists worry about the cost of the treatments ― and the resulting impact on federal and private insurance plans ― if they win approval from the Food and Drug Administration. Each medicine is expected to cost at least $1 million to $2 million, not including the expense of administering them and other aspects of the treatment. That rivals the seven-figure prices of a handful of other recently approved gene-based therapies for rare inherited diseases.

It also remains to be seen how durable the benefits of the therapies are. Researchers plan to follow trial volunteers for 15 years after treatment.

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Nonetheless, the influential Institute for Clinical and Economic Review, or ICER, an independent Boston-based drug-pricing watchdog, said either therapy could go for nearly $2 million and be worth it, given the cumulative costs of treating sickle cell over a lifetime and the benefits the new approaches would bring to patients and families.

“From the earliest days of gene therapy, patients, families, and clinicians have imagined that someday it might be possible to address the underlying genetics of sickle cell to achieve a cure,” Dr. David Rind, ICER’s chief medical officer, said in April when the group issued a draft report that it plans to update next month. “These first two genetic therapies, using different technologies and altering different genetic targets, may mean that day has nearly arrived.”

Dvaizea Moore gave his young son, Jacob Moore, a gentle touch, as Jordan Wright held Jacob. Meg McKinney for The Boston Globe

Boston-based Vertex and CRISPR Therapeutics, which is headquartered in Switzerland but has 400 of its 500 employees in Massachusetts, announced that they applied for FDA approval in early April. They expect a decision by Dec. 8. Somerville-based Bluebird applied for approval in late April and has said it hopes to market its gene therapy early next year.

Sickle cell is a group of inherited blood disorders that affect hemoglobin, the oxygen-carrying protein in red blood cells. It occurs in about one out of 365 Black births in the US, and one out of 16,300 Hispanic American births, according to the Centers for Disease Control and Prevention. Millions of people worldwide have the condition. White people are rarely diagnosed with it.

The disease causes round, flexible red blood cells to deform into a sickle shape and stick to vessel walls. That deprives tissues of oxygen, resulting in pain and often necessitating blood transfusions. The blocked blood flow can also lead to strokes, damage organs, and cause early death. A 2019 study in JAMA Network Open estimated the life expectancy of adults with sickle cell in the US is 54 years, about 20 years shorter than the general population.

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People with sickle cell inherit two faulty hemoglobin genes ― one from each parent. If someone inherits just one defective copy, that person is said to have sickle-cell trait but can lead a normal life. Indeed, having the single faulty gene appears to serve an evolutionary purpose; it confers protection against severe cases of malaria, the life-threatening disease spread by mosquitoes. Sickle cell trait is more common in people of African descent, whose ancestors come from tropical regions where malaria is endemic.

Nearly three-quarters of a century ago, renowned biochemist Linus Pauling and several collaborators wrote a classic paper that identified a structural flaw in the hemoglobin of people with sickle cell. It marked the first time scientists provided a molecular explanation for a disease and helped to usher in the field of molecular medicine.

In the years that followed, however, efforts to develop disease-modifying treatments moved slowly, particularly compared with those for other inherited disorders. That disparity, many specialists say, reflects persistent racial inequities in health care.

“If this was a disease of white people, we would have cured it decades ago,” said Dr. Sharl Azar, a hematologist at Massachusetts General Hospital and medical director of its Comprehensive Sickle Cell Disease Treatment Center.

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That bias has affected everything about the treatment of the disorder, specialists say, including how much federal funding sickle cell research has received, the number of drugs approved, even how medical personnel at hospital emergency rooms sometimes respond skeptically to patients seeking opioid medications to relieve debilitating pain.

“I feel sorry for you sicklers because you’ve become addicted to pain medicine,” Gray, the recipient of the CRISPR treatment, recalled an emergency room nurse in Mississippi telling her when Gray was in agony. Many people with sickle cell disease consider the word “sickler” offensive.

To illustrate the disparities between sickle cell and other genetic maladies, experts often cite cystic fibrosis, another inherited, progressive, and life-threatening condition, but one that afflicts mostly white patients.

Dvaizea Moore shows some of the prescribed medications he takes for sickle cell disease.Meg McKinney for The Boston Globe

Cystic fibrosis, which results in a thick, sticky buildup of mucus in the lungs and other organs, is about one-third as common as sickle cell disease in the US. Yet it has received 7 to 11 times the federal and foundation research funding per patient, according to a 2020 article in the New England Journal of Medicine. (Foundations rely on charitable contributions, and Black Americans historically have less access to intergenerational wealth.) Meanwhile, the FDA had at the time of the article cleared four medications for sickle cell, compared with 15 for cystic fibrosis, including four expensive blockbuster drugs from Vertex.

Dr. Patrick McGann, who co-wrote the article and runs sickle cell programs at Rhode Island Hospital and Hasbro Children’s Hospital in Providence, noted that it wasn’t until 1972 that the federal government began funding the fight against the disease after President Richard Nixon cited a “sad and shameful” history of neglect.

Vertex itself has acknowledged that sickle cell patients have historically been marginalized. Last year the company and the nonprofit Vertex Foundation earmarked $50 million over five years for programs to address racial inequities in health care, including a $2 million gift to the Mass. General sickle cell treatment center.

For decades, the only potential cure for sickle cell has been a transplant of bone marrow from someone whose body makes normal hemoglobin. But the procedure can be risky and is usually reserved for patients with a healthy sibling to provide normal bone marrow cells. Only about 15 to 20 percent of patients have a suitable match.

In 1998, the FDA approved hydroxyurea, the first disease-modifying drug, but it doesn’t work for everyone.

In contrast, the two gene-based therapies seek to permanently fix the DNA of damaged blood cells in people with the disease with a single infusion.

The medicine from Vertex and CRISPR is called exa-cel and would be the first US-marketed treatment based on CRISPR, the revolutionary Nobel Prize-winning gene-editing technology. It works by editing a patient’s bone marrow cells to make high levels of fetal hemoglobin ― the healthy, oxygen-carrying form of hemoglobin produced during fetal development that is replaced by adult hemoglobin soon after birth.

Unlike adult hemoglobin, fetal hemoglobin resists forming a crescent shape in sickle cell patients, and scientists have long wanted to find a way to restart it. The discovery of CRISPR in 2012 made it possible to flip the genetic switch, with what appears to be remarkable effect. Sixty days after their genes were edited in the Vertex-CRISPR trial, 16 of 17 sickle cell patients were free of pain crises. That relief has lasted at least a year and as long as three years so far, according to the latest data from the firms on Friday.

Vertex and CRISPR have also tested the treatment for beta thalassemia, a related but rarer blood disease, with similarly impressive results.

Dvaizea Moore congratulated his son, Jacob Moore, for bringing a football to him, during a front yard session. Moore recently received an experimental gene therapy made by Bluebird Bio for sickle cell disease.Meg McKinney for The Boston Globe

Bluebird’s sickle cell therapy is called lovo-cel and works differently. It uses an engineered virus to insert a modified gene into the DNA of a patient’s blood stem cells. The healthy gene enables cells to produce a form of adult hemoglobin that has anti-sickling properties. Richard Colvin, Bluebird’s chief medical officer, said 97 percent of patients who received the therapy haven’t had pain that required hospitalization since the treatment, and 90 percent haven’t had any pain.

Both therapies for sickle cell require patients to undergo a round of chemotherapy to make room in their bone marrow for the genetically altered cells that produce healthy hemoglobin. That can be an ordeal.

Moore, the Alabama man in the Bluebird trial, said the chemotherapy temporarily darkened his skin, caused painful sores in his mouth, and made his hair fall out.

Nonetheless, he said, the side effects were a small price to pay for the relief from sickle cell. He no longer needs blood transfusions, which he used to receive every four weeks. And his pain episodes, which felt like his bones were breaking, are gone. “I feel like a brand-new person,” he said.

As promising as the rival therapies are, some sickle cell patients say they aren’t interested in them, at least partly because they already have been hospitalized so many times and the disease has taken an irreversible toll on their bodies.

Dima Hendricks, a 41-year-old patient who lives in Brockton and counsels others with sickle cell, began participating in the trial of another gene therapy developed at Boston Children’s Hospital in 2018. But she had to drop out because of a blood clot that went to her heart. She had open heart surgery and spent two months at Brigham and Women’s Hospital.

Not long afterward, Hendricks said, she started taking a newly approved once-daily pill called Oxbryta that boosts hemoglobin and is made by a Pfizer subsidiary. Although the drug is not a cure, she has been hospitalized only twice since then and feels more energetic.

“I’m happy that they’re finally coming up with some curative therapies for sickle cell disease,” she said of the gene-based treatments. “I do hope they get approved so there can be options for younger people. But people living with sickle cell disease for, like, 30 years-plus, we need to err on the side of caution. It’s riskier for individuals that are older like me because we have so much damage to our bodies.”

Dima Hendricks sat at her home in Brockton on June 6, 2023. Hendricks has sickle cell disease and is an advocate for people with the disorder. She says patients should be cautious about undergoing gene-based treatments if they are approved by the FDA. Erin Clark/Globe Staff

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com.