Scientists cured sickle cell. Then their next challenge began.

Ian Wilhite’s life was completely circumscribed by his sickle cell anemia. Since childhood, he calculated energy expenditures like a seasoned accountant—how many hours of sleep he needed, which cities were safe to visit, which jobs he could realistically hold. Still, Wilhite finished law school and worked demanding jobs while he quietly navigated a disease that was slowly dismantling him from the inside.

The sickled cells deprived his vital organs of oxygen, steadily damaging his bones and heart while triggering increasingly frequent pain crises that landed him in the emergency room every other weekend. By his mid-twenties, he had already replaced a hip; a few years later, a shoulder. “I knew I was getting progressively worse,” says Wilhite, “but you have to stay positive, knowing that more pain could be around the corner—or a stroke.”

When the FDA approved two gene therapies for sickle cell disease in December 2023, Wilhite called his hematologist the next morning. He was ready.

But the treatment regimen consumed most of a year—requiring a dedicated caregiver, weeks away from employment, months of restricted activity, and the ability to travel to more than 50 qualified centers, which have passed muster by the manufacturers—Bluebird Bio for Lyfgenia, and Vertex Pharmaceuticals for Casgevy—and are often concentrated in major cities and academic medical hubs.

His stem cells were collected and genetically edited before doctors destroyed his bone marrow with five days of chemotherapy to make room for the corrected cells. But the side effects from the chemo are brutal: it strips the lining of the digestive tract, causing mucositis so severe that swallowing becomes impossible, and wipes out the immune system, forcing patients to be quarantined for weeks so they won’t be sickened by even a common cold. Wilhite lost 30 pounds in the month he spent in the hospital.

Fortunately, his parents were retired. They drove from Austin, Texas, to the University of Kansas Medical Center and took shifts at his bedside. Barely 100 days out from receiving the altered stem cells, his symptoms vanished. He has not had another pain crisis.

“I didn’t realize how much effort I’d been putting into just planning my day,” says Wilhite, who’s now 38. “Just to get from A to B to sleep. It’s a huge weight that’s off.”

For Wilhite, every piece had fallen into place: employer-based insurance, retired parents who could become full-time caregivers, and the geographic luck of living within a day’s drive to one of the country’s few qualified treatment centers. He was the ideal gene therapy patient—not because his disease was less severe than anyone else’s, but because everything surrounding it aligned with exceptional rarity.

“The biggest chokepoint is societal,” says Mark Walters, director of the Blood and Marrow Transplantation program at UCSF Benioff Children’s Hospital Oakland, “and the need for an engaged, resourced family, people who can take time off to be a caregiver.” For most of the 100,000 Americans living with sickle cell disease, those conditions simply don’t exist.

The obstacle is no longer the science. It’s delivery. Both approved treatments are ex vivo gene therapies, meaning a patient’s blood-forming stem cells must be removed, genetically edited in specialized laboratories, and returned after chemotherapy destroys the existing bone marrow.

Because every treatment is manufactured from a patient’s own cells, even experienced hospitals can treat only a handful of people each year. In the first year after FDA approval, fewer than 100 patients nationwide received either Casgevy or Lyfgenia, according to year-end reports from both companies, despite price tags ranging from $2.2 to $3.1 million per patient.

This is the central paradox researchers are now racing to resolve: how do you preserve the precision that makes gene therapy work while building something that resembles, in scalability and cost, a conventional medicine?   

“Sickle cell is a use case for what gene therapy at scale really means,” says Julie Kanter, a hematologist at the University of Alabama in Birmingham who has spent her career treating sickle cell patients and studying why transformative therapies fail to reach them. “The pay-off is tremendous—patients get to live a normal life—and the momentum is real. We are now working through, in real time, how to make this work not just for the exceptional, but for everyone.”

Why sickle cell became gene therapy’s first test

Researchers have long viewed sickle cell disease as the ideal proving ground for gene therapy because it stems from a single genetic mutation and its blood-forming stem cells can be removed, edited, and returned to the body.

Sickle cell disease begins with a single misprint in the genetic code. When oxygen levels drop, the faulty hemoglobin causes red blood cells to stiffen into rigid crescents that block blood flow, triggering excruciating pain and progressive organ damage.

Babies are initially protected because they produce fetal hemoglobin, which does not sickle. Once that protection fades during infancy, symptoms emerge. That biological quirk is the foundation of today’s gene therapies.

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Neither approved treatment corrects the original mutation. Instead, both restore fetal hemoglobin production, allowing healthy hemoglobin to override the disease. Casgevy uses CRISPR-Cas9 to disable the genetic switch that suppresses fetal hemoglobin, while Lyfgenia inserts a modified hemoglobin gene using a viral vector.

That precision, however, comes at a cost. At $2.2 million to $3.1 million per patient, each treatment is custom-manufactured from a patient's own stem cells and cannot be reused or mass-produced.

Roughly half of sickle cell patients in the United States are covered by Medicaid, leaving state programs ill-equipped to absorb million-dollar, one-time therapies. In January 2025, the Centers for Medicare and Medicaid Services launched a voluntary outcomes-based payment model that allows states to negotiate directly with manufacturers, spread costs over time, and receive rebates if treatments fail to deliver as promised, according to the Department of Health and Human Services. Thirty-three states opted in—“it’s meaningfully broadened access,” says Walters—but progress has been slower than hoped.

Eligibility presents another barrier. Several clinical trials currently cap enrollment at 40, due to concerns about whether older patients can tolerate chemotherapy required before treatment. Wilhite, at 38, barely made the cutoff. His older sister, Ava, who also has sickle cell, is 42 and does not qualify. It’s frustrating “to have this disease,” says Wilhite, “and then have a cure just beyond reach.”

The next wave of gene editing

If the first generation of gene therapies proved that editing DNA could cure sickle cell disease, researchers are now trying to make those edits even more precise.

In 2016, David Liu’s lab at Harvard’s Broad Institute developed base editing—a refinement of CRISPR that makes a precise chemical change to a single DNA letter, correcting the tiny genetic errors that cause thousands of human diseases. “You’re changing the misspelled letter into the correct one,” says Liu.

Beam Therapeutics, the company Liu co-founded, launched the BEACON clinical trial to test whether base editing could safely activate fetal hemoglobin in people with sickle cell disease.

In December of 2023, Branden Baptiste was the first patient in the world to receive the experimental treatment.

By the time the Boston native entered the trial at age 19, the disease had already exacted a steep toll. He had endured years of debilitating pain crises, undergone bilateral hip replacements, survived acute chest syndrome, and relied on daily medications to keep the disease at bay. “My life was crashing downhill,” says Branden. “I was well on my way to dying.”

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At Boston Children’s Hospital, he went through the same chemotherapy conditioning that Casgevy patients endure and was infused with the edited cells. In the two years since, he has been pain-free, is off all sickle cell–related medication, and is training to be an aviation technician. Beam Therapeutics has since treated more than 30 patients in the BEACON trial, and each one reported a similar result, according to a New England Journal of Medicine study in April. “I’ve never felt better,” says Branden, “and now I actually have hope for survival.”

Researchers are now pursuing an even more ambitious goal: correcting the sickle cell mutation itself. Late last year, a clinical trial launched a therapy developed by researchers at UCSF and Oakland Children’s Hospital that aims to repair the single misspelled DNA letter responsible for the disease. The approach achieves correction in roughly 25 to 40 percent of stem cells, compared to 80 to 90 percent in the approved therapies. Whether correcting a smaller percentage of stem cells will produce the same clinical benefit remains an open question.

The next leap

Yet even these next-generation editing tools inherit the same logistical burden. They are ex-vivo: cells must be removed from the body, edited in specialized laboratories, and infused back into patients after intensive chemotherapy conditioning.

The ultimate goal is in vivo gene editing: delivering the editing machinery directly into the patient’s body, without ever removing cells. The transport vehicles are lipid nanoparticles—tiny spheres of fat, similar to those used in mRNA COVID-19 vaccines— engineered to carry gene-editing tools directly into target cells.

Instead of a months-long process requiring specialized manufacturing, an in vivo gene therapy could be manufactured at scale, stored like a conventional drug, and administered at a far broader range of hospitals. “You would simply drip fat bubbles containing the editing agent through an IV,” says Liu.

Avoiding chemotherapy could also spare patients infertility—one of the major reasons families decline today’s treatments, according to Jennifer Adair, vice chair of the department of genetic and cellular medicine at UMass Chan Medical School.

In 2024, a baby known as KJ Muldoon, born with a fatal hereditary liver enzyme disorder, became the first patient to receive a customized in vivo CRISPR therapy, marking the first successful use of the technology inside the human body. The treatment delivered gene-editing machinery directly into his liver cells—without removing a single cell from his body. His physicians now believe KJ will live a normal life.

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Researchers at the Children’s Hospital of Philadelphia are now developing a flexible, standardized platform that uses the same gene-editing technology across related genetic mutations. This enables them to pool safety and efficacy data to clear FDA review without starting from scratch each time. “For certain classes of disease, you can make one kind of edit that benefits many patients, even those with different underlying mutations,” says Liu.

Last year, during the annual meeting of the American Society of Hematology, Tessera Therapeutics reported in non-human primates that a single lipid nanoparticle infusion corrected enough blood-forming stem cells to produce curative levels of fetal hemoglobin—an encouraging step toward eliminating stem cell transplants and chemotherapy altogether.

This result is “remarkable,” says Adair, who expects multiple companies will initiate human trials within the next year. “There is an incredibly large amount of unexplored runway between where we are right now and the optimal future treatment, which is essentially the shot-in-the-arm in vivo correction,” she adds. “But the timeline is real.”

For Wilhite, the next breakthrough won’t be measured by a more precise gene edit. It will come when patients like his sister no longer have to watch a cure remain just beyond reach.