Gene therapy for sickle cell disease treatment brings hope to patients

DACULA, Ga. — For as long as he can remember, Jimi Olaghere felt he was destined to be a father. “It’s so true in my soul,” he told his wife, Amanda, when they struggled to get pregnant. But when they were finally expecting a baby boy in 2019, joy was tinged with despair.

For 34 years, sickle cell disease had been hammering Jimi’s body and stealthily shredding his ambitions. He knew it would come for his dream of being a dad, too.

Inside Jimi, normally pliable, disc-shaped red blood cells deformed into rigid crescents. Those microscopic sickle-shaped cells clumped together, unleashing a cascade of damage. Pain was a constant, but about once a month it erupted into pure agony — like glass had shattered inside his veins and shards were sawing back and forth.

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How would monthly trips to the emergency room to manage his pain work with a newborn baby? Could he keep up with a toddler when everyday pain could keep him stuck in bed all day? Would he even live long enough to try?

“I knew sickle cell would win that battle as well,” Jimi said. “It won everything — with my career, with education, with everything I wanted to do.”

Then, midway through Amanda’s pregnancy, the couple read an article about Victoria Gray, a woman whose genes had been experimentally edited to treat her sickle cell disease. It was still too soon to know exactly how well it worked, but Jimi wanted in.

After decades of neglect, stigma and underfunding, sickle cell is getting the equivalent of the red carpet treatment in science. It’s the target of a competitive biotech race, with scientists and companies using a crop of cutting-edge tools to try to cure the debilitating illness.

The first gene therapies for sickle cell, including one based on the buzzy, Nobel Prize-winning technique called CRISPR, will be reviewed by regulators this year, and companies are preparing to launch the medicines if they get the green light. That puts the country at the cusp of two frontiers: a new era in treating a tragically overlooked disease, and the beginning of what could be a CRISPR revolution in medicine.

It’s a dramatic about-face for sickle cell patients, who have often felt abandoned by the medical system. The rare disease afflicts about 100,000 people in the United States, most of them Black. Racism at both the institutional and interpersonal level has stymied funding and alienated patients, who are often treated as drug-seekers when they show up in emergency rooms in acute pain.

“Of course there’s skepticism. This is a disease that’s been left to just succumb to the health-care system for so long, and suddenly this influx of money and parties and pharmaceutical companies [and] a whole staff of White folks want to come in and ask us about our disease,” said Ashley Valentine, president of Sick Cells, a patient advocacy group that she founded with her brother Marqus, who died of a hemorrhagic stroke at age 36.

There are risks and unknowns with any new technology; one doctor told Jimi the magnitude of the challenge was comparable with landing on the moon for the first time. But the doctors, patients and others eager for sickle cell treatments say that turning gene editing into a viable therapy, then finding ways to make it widely accessible, will help carve a path for others to follow.

“The hope,” said Valentine, “is that if the feds and governments and society can figure this out with sickle cell, they can figure this out with other diseases.”

A long time coming

Decades before Jimi was born, chemist Linus Pauling discovered the root of the problem in sickle cell disease: an atypical form of the oxygen-carrying hemoglobin protein inside red blood cells. He dubbed sickle cell the first “molecular” disease — a new paradigm that would shape biomedical research for decades.

Hard scientific work would fill in the rest of the story. The human genetic code is a string of 3 billion letters, each representing one of four molecular building blocks. Atypical hemoglobin is the result of a misspelling in one gene — a T where there should be an A. People with just one copy of the altered gene have “sickle cell trait.” They live without major health symptoms, and even have an advantage: better protection against malaria. But people with two copies can experience devastating symptoms and die decades early.

Jimi’s parents had sickle cell trait. So did an older sister. But he had sickle cell disease. As a child growing up in Nigeria, it was hard to keep up with his friends’ energy levels. The pain episodes would arrive at night, or after tough exertion. His parents used menthol rubs and over-the-counter painkillers to try to ease his discomfort, which was so intense he would pass out.

Eventually, Jimi moved to live with relatives in New Jersey so that he could take advantage of better medical care. At a sickle cell support group, Jimi began to understand how deeply the disease infiltrated every aspect of daily life. It wasn’t just hospitalizations and pain. A girl shared that she would eat random objects — a condition called pica that often accompanies the disease. He recognized his own tendency to scrounge chalk and rubbish to eat, which had always made him feel as if he were going crazy.

The disease often gets worse as patients get older, which tragically coincides with a medical cliff in the U.S. health-care system. Children have parents and pediatric hematologists who are devoted to managing their disease. As adults, they have to coordinate their own care and are often treated very differently. Most people who have the disease in the United States are Black, and they are often met with suspicion and hostility, not compassion — when they show up in the emergency room in excruciating pain.

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As he got older, Jimi’s pain episodes became so frequent that they bled together in his memory. One time, his fever spiked so high that he lost consciousness. Jimi woke up in the intensive care unit a day later, disappointed to still be alive.

“There became a point of my life — I stopped going to the emergency room and started medicating at home,” Jimi said. “I was just so embarrassed.”

He suffered a heart attack in his 20s. He developed blood clots in his lungs. His hips sometimes ache because parts of the bone tissue in his joints died because of lack of oxygen delivery.

Until recently, there weren’t many treatments for sickle cell disease. A bone-marrow transplant could cure it by providing patients with marrow that made normal hemoglobin, but a suitable match from a sibling could be found for only about 1 in every 5 patients. Then there’s hydroxyurea, the first and only drug that was approved to treat sickle cell until 2017; three drugs have been approved since then. Hydroxyurea helps keep red blood cells from sickling, or deforming into a sickle shape, by increasing levels of a type of fetal hemoglobin that is switched off after birth.

Research into the disease gave scientists two main avenues for gene therapy. One would be to replace the gene or correct the genetic typo to restore normal hemoglobin production. Another would be to get the body to start pumping out fetal hemoglobin again.

The ideas were straightforward, but progress was slow. The field was underfunded, in part because the Black population historically lacks access to the intergenerational wealth, influence and privilege that fuels private philanthropy for rare-disease research. Even at the federal level, other rare diseases that cut short people’s life spans — such as the lung disease cystic fibrosis — received triple the funding per person until the gap began to narrow in 2017.

“There’s huge underinvestment,” said Stuart Orkin, an expert in the field and professor of pediatrics at Harvard Medical School and the Dana-Farber Cancer Institute. “The NIH probably wouldn’t like me to say this, but one of the goals of the National Heart, Lung and Blood Institute is to cure sickle cell disease. They certainly have not put the kind of resources into it that would be required.”

Gary Gibbons, director of the NHLBI, pointed to data showing that federal funding for sickle cell research has doubled since 2010, and he highlighted the Cure Sickle Cell Initiative that was launched in 2018. “NHLBI is committed to improving the care and long-term survival for children and adults with sickle cell disease in the U.S. as well as other parts of the world,” Gibbons said.

A turning point occurred when sickle cell became an attractive target for companies to invest in — as new gene therapy techniques reached prime time and better understanding of the disease clarified the best therapeutic strategies.

Fifteen years ago, scientists pinpointed a gene called BCL11A that worked like a dimmer switch, controlling the amount of fetal hemoglobin the body produced. When scientists shut it off, fetal hemoglobin expression turned back on. In 2011, Orkin’s lab showed that it was possible to reverse sickle cell disease in mice by flicking the BCL11A switch.

At the same time, a growing array of gene therapy techniques gave scientists tools to flip genetic switches or insert new genes — kicking off a flurry of competing sickle cell cures. CRISPR, discovered in 2012, is being used to edit a key region of the BCL11A gene to turn fetal hemoglobin back on. Other approaches use a harmless virus as a kind of Trojan horse to insert a new version of the hemoglobin gene that resists sickling into a patient’s stem cells. Yet another uses a specialized RNA molecule to silence BCL11A.

After years of little progress, there wasn’t just one way to treat sickle cell — there were many.

“I have wanted to see this succeed for 40 years,” said Francis Collins, the former NIH director whose postdoctoral research in the early 1980s was on sickle cell. “I thought we’d be lucky if in my lifetime, if we achieved even a single cure of someone for sickle cell disease.”

‘Out of nowhere, I could tell it was gone’

For most of his life, Jimi had a hard time envisioning the future. How many times had people told him he wouldn’t live to see his 20th or 30th birthday? On his first date with Amanda, when they were in their early 20s, he put down the menu and told her he had sickle cell, and that he understood if that was a dealbreaker.

“I’m super competitive, and I said, ‘I’ll take it on,’” Amanda recalled, laughing. She went home and began Googling to learn more about the disease.

To manage Jimi’s sickle cell, the couple forged a powerful partnership. They could handle anything together. But with a baby on the way, the stakes changed.

“I thought I was going to die,” Jimi said. “I thought, ‘I can’t leave my wife with a son and not be here for them.’”

In November 2019, Jimi and Amanda flew to Nashville to meet with Haydar Frangoul, the pediatric hematologist leading a trial of a CRISPR gene therapy for sickle cell disease at Sarah Cannon Research Institute. They learned shortly after Christmas that Jimi qualified for the trial. Their son, Sebastian, had just been born. It felt like a gift.

From start to finish, Jimi’s treatment would take the better part of a year. First, his stem cells needed to be collected from his blood. This required long car trips to Nashville and being hooked up to a machine for hours at a time. Once the researchers collected enough stem cells, they edited the cells to disable the BCL11A switch. Then the cells needed to be carefully checked for quality.

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Jimi also needed chemotherapy to kill off existing cells in his bone marrow so that his edited stem cells would have room to engraft and grow. His hair fell out and he developed painful sores in his mouth.

Amanda, Jimi and baby Sebastian lived in the hospital for weeks, juggling remote work and the haze of starting their new family life. They set up a playpen in the hospital room. The nurses and doctors became like a second family. Jimi continued to run his e-commerce business from his hospital bed, while Amanda worked remotely, sometimes rushing to a nearby hotel room to do conference calls. Sebastian often napped next to his dad.

When Jimi’s body was ready to receive the cells, the nurses brought three syringes into the room. Another participant in the trial had warned him: It will smell like creamed corn. Sure enough, the room filled with the aroma, due to a preservative used to freeze the cells. His parents watched through a live feed from Nigeria.

Jimi came home at the end of November 2020. As his new edited cells began pumping out fetal hemoglobin, he felt the disease depart.

“I had lived 35 years with this disease that sometimes I consider a companion, and out of nowhere I could tell it had gone — or was in the process of leaving. We were enmeshed together, and I could feel it detangling,” Jimi said.

A year went by, and Jimi had no pain crises.

“We can plan in the future — like decades in the future now,” Amanda said. They got pregnant again using in vitro fertilization, this time with twins.

‘Carry your cure with you’

Jimi is one of 31 participants whose results have been made public in the sickle cell trial run by Vertex Pharmaceuticals and CRISPR Therapeutics. None have had pain crises since their treatment, according to data through February 2022, though at that time, only 11 patients had been followed for at least a year. The companies just finished submitting data to regulators, and the Food and Drug Administration is expected to make a decision on whether to approve the therapy as soon as this year. The therapy is also being tested in the related blood disease beta thalassemia.

Another trial run by Massachusetts-based company Bluebird Bio uses a different gene therapy approach. A patient’s stem cells are removed, then a virus inserts a gene into them that codes for a non-sickling version of beta-globin, a component of hemoglobin. Bluebird has treated 50 sickle cell patients, six of whom have been followed for six years, and submitted its data to regulators in April. The company has announced it could roll out the therapy in 2024.

The beauty of gene editing for sickle cell is that it takes a lot of the luck out of the equation. People don’t have to count on finding a bone marrow match. They also don’t have to worry about a dangerous complication that can occur when cells transplanted from another person attack the recipient’s own tissues.

“You carry your cure with you, basically,” the Sarah Cannon Research Institute’s Frangoul said.

But the challenges of turning an intensive therapy into an accessible medicine are formidable. For instance, chemotherapy is not only time-intensive and unpleasant, but it also causes infertility, meaning patients must have the ability to put their lives on hold for the treatment and have the time and resources to make long-term plans about future reproductive choices.

The first gene therapies for sickle cell will be a turning point, but it will take years — and many millions of dollars — to reach even a fraction of the patients who could benefit. Jimi did not have to pay for his treatment because it was part of a clinical trial, and the companies have not yet announced the price tag. A draft report by the Institute for Clinical and Economic Review, a nonprofit that examines whether drugs merit their prices, found that charging $2 million per treatment could be cost-effective for patients with severe disease, leading to health gains and lifetime opportunities.

Already, the success of the front-runners is winnowing out competition, as some companies drop their sickle cell gene therapy programs. The trend disappoints scientists who worry that a winner-takes-all model will leave important scientific questions unsettled about which approach is superior.

Jimi says he feels like he’s cured, though he knows it isn’t the correct word. Frangoul will follow Jimi and other patients for 15 years to track their health and monitor them for side effects.

Two patients in Bluebird’s trial developed acute myeloid leukemia and died; extensive studies found that the cases were not likely to be related to the insertion of the new gene.

If both of the therapies being submitted are approved, they probably will be limited to severely ill people at first. Vertex officials estimate there are about 25,000 people in the United States in that category, and they have outlined plans to partner with 50 treatment centers in the United States and 25 in Europe.

“I’m excited — but I don’t expect to see my job different two years from now because we have a gene therapy,” said John J. Strouse, a hematologist at Duke University School of Medicine who treats adult sickle cell patients.

Frangoul said the questions of access and insurance coverage already worry him. He recalled the early days of bone marrow transplants to treat sickle cell, when he would write appeal after appeal to insurers to try to get the novel procedure covered.

Jennifer Doudna, the biochemist at the University of California at Berkeley who shared the Nobel Prize for discovering CRISPR, said that she anticipates feeling “sheer joy” when the first CRISPR therapy is approved, but also urgency.

A nonprofit she founded, the Innovative Genomics Institute, is working on a different CRISPR therapy to correct the genetic typo in sickle cell disease. Institute leaders also hope to pioneer a less-conventional business model in which creative partnerships between industry, government, academia and nonprofits could lead to new ways to price very expensive drugs for rare diseases.

“I think it’s going to make me feel even more motivated,” Doudna said. “People need this therapy, right? And … people can’t pay millions of dollars for it.”

A new life

After Jimi’s treatment, he had a different kind of crisis: Who am I without sickle cell?

After a lifetime of constant pain, it was disconcerting to have none. He felt guilty for not being elated that he was finally well, but he mourned the years of lost potential that he had spent as a prisoner of sickle cell.

“The physical toll of the disease sickle cell itself doesn’t compare to the emotional vacuum it creates,” he said.

At the same time, he looks at his life now with a bit of wonder.

He stands a little taller, and he no longer wears glasses to obscure his eyes, which were severely jaundiced because of the disease. After years of being unable to sleep at night because of pain and taking naps during the day, he wakes up at 4:30 a.m. feeling like he chugged a Red Bull. He meditates, works, then wakes his twin daughters, Eloise and Willow, and gives them breakfast. The soundtrack in his household is kid-friendly songs and discussions of dinosaurs.

“To me, it still feels special — the amount of energy I have,” he said.

The story doesn’t end with him. Some of Jimi’s relatives in Nigeria have sickle cell disease. Three of Jimi’s children are carriers of the sickle cell trait. He wants to make sure other people with sickle cell have the opportunity to free themselves from the disease — not only the patients in the United States, but also the 20 million people in the rest of the world, many of them in sub-Saharan Africa, India and the Middle East.

Extending gene therapies to more populations will require big leaps in science. A major quest is on to invent ways to deliver gene therapies without an intensive bone marrow transplant. And Jimi wants people in the next generation, regardless of where they live, to have the opportunity to grow up without the shadow of illness.

“If by God’s grace we cure 100,000 people [in the United States], that’s not even a fraction of the people that actually suffer with the disease in West Africa, India and all those regions where it’s quite prevalent,” Jimi said. “Most of my advocacy is shining a light to all of these places that … are still in the background for now.”

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