A Gene Therapy Cure for Sickle Cell Is on the Horizon

Two life-altering treatments could soon be available, but questions remain about how accessible and affordable they’ll be.

Evie Junior’s life has been defined by pain. He was born with sickle cell disease, which causes red blood cells to be sticky and C-shaped, not smooth and round. These cells are supposed to move freely through blood vessels, carrying oxygen to the body. But in people with this inherited form of anemia, they clump together and block blood flow. This triggers excruciating episodes known as pain crises, which can happen anywhere in the body and last for hours or even weeks. The disease damages organs over time and can cause strokes and early death. 

People with sickle cell are often fatigued because their red blood cells die fast, cutting off oxygen to the body. Strenuous exercise, sudden temperature changes, and dehydration can also trigger a pain crisis. Growing up in the Bronx, in New York City, Junior recalls getting winded easily and having to be careful when playing sports or swimming. The pain was so bad that he often missed school.

As an adult, it didn’t get easier. Sometimes he could ward off the pain with ibuprofen and get back to work the next day. But every few months, a severe crisis sent him to the hospital. Things got so bad that in 2019, he enrolled in a clinical trial at the University of California, Los Angeles, which has been testing a gene therapy to cure sickle cell. It involves genetically modifying patients’ blood-forming stem cells in the lab so that they can produce healthy red blood cells. The procedure is experimental. Junior knew there was a chance it wouldn’t work. “I felt like it was time for a Hail Mary,” he says. “My entire life up until that point was being sick.”

In July 2020, he received a one-time infusion of his own altered stem cells. Three months after the treatment, tests showed that 70 percent of his blood cells had the intended change—far above the threshold needed to eliminate symptoms. He hasn’t had a pain crisis since. He can do more outdoor activities, and he doesn’t have to worry about missing work. He plans to go skydiving soon—something he never would have dreamed of doing before. “My quality of life is so much better now,” he says.

Junior, who's now 30 years old, is one of dozens of sickle cell patients in the US and Europe who have received gene therapies in clinical trials—some led by universities, others by biotech companies. Two such therapies, one from Bluebird Bio and the other from Crispr Therapeutics and Vertex Pharmaceuticals, are the closest to coming to market. The companies are now seeking regulatory approval in the US and Europe. If successful, more patients could soon benefit from these therapies, although access and affordability could limit who gets them.

“I’m optimistic that this will be a game-changer for these patients,” says Cheryl Mensah, a hematologist at Weill Cornell Medicine and New York-Presbyterian Hospital, who treats adults with sickle cell disease. “If more patients undergo curative therapies, especially at younger ages, there will be fewer adults who have chronic pain and fatigue.”

Sickle cell disease affects around 100,000 people in the US, and millions around the world. The vast majority are of African ancestry, but the disease also affects Hispanic people from Central and South America and those of Middle Eastern, Asian, Indian, and Mediterranean descent.

In the 1970s, few children with sickle cell disease survived to adulthood. Today, the average life expectancy is 54 years in the US, but that’s still 20 to 30 years less than most people. “This disease disrupts life significantly,” says Markus Mapara, professor of medicine and director of the Blood and Marrow Transplantation Program at Columbia University Medical Center, one of the sites of the Bluebird Bio trial.

The disease arises from a genetic mutation in the HBB gene, which makes hemoglobin, the protein that carries oxygen to organs. We all inherit two copies of the HBB gene—one from each parent—and people with sickle cell disease received a mutated copy from both. People who inherited the mutation from just one parent typically have no symptoms, since the other provided a healthy backup copy of the gene that produces normal blood cells. 

The genetic root of the disease was discovered in the 1950s, and as early as the 1960s, scientists started speculating that adding working copies of genes to patients’ cells could treat—or perhaps even cure—sickle cell and other genetic diseases. But first they had to solve the problem of how to shuttle genetic material into cells. In the 1970s, researchers realized they could use viruses to do this; by their nature, viruses are good at infecting cells. 

Then, in 1984, doctors inadvertently cured a child of sickle cell while trying to treat her for another disease: leukemia. They used a bone marrow transplant, also known as a stem cell transplant. The procedure involves extracting stem cells from a healthy donor’s marrow and infusing them into the recipient’s bloodstream. The stem cells migrate to the bone marrow, where they gradually form new, healthy blood cells. To this day, it remains the only FDA-approved cure for sickle cell disease, but it requires a full sibling donor with compatible bone marrow, and only about 20 percent of patients have one. It’s also risky. A transplant can cause infection or graft-versus-host disease, a condition in which the donor stem cells attack the recipient’s organs and tissues.

In the intervening decades, researchers kept chipping away at gene therapy. They tried different ways of modifying the hemoglobin gene, and used different engineered viruses, known as viral vectors, to sneak it into cells. “No one knew what was going to work,” says Donald Kohn, a physician and professor of microbiology, immunology, and molecular genetics and pediatrics at UCLA, who developed the treatment Junior received. Early versions of gene therapy didn’t work because the new gene often didn’t make its way into enough stem cells. 

But a breakthrough came in 2001, when a team from Harvard and MIT reported that they cured a mouse using gene therapy. It would take another 16 years for gene therapy to do the same for a person.

Today, a handful of these therapies have reached human clinical trials. Both UCLA’s and Bluebird Bio’s approaches add a modified version of the HBB gene to patients’ own stem cells. The altered cells are then infused back into the patient, like in a bone marrow transplant, so they can take up residence and start making normal hemoglobin.

UCLA researchers have so far treated three patients, including Junior. In the two other patients, not enough corrected cells took hold to eliminate pain crises. The team plans to treat a fourth patient this summer with a modified protocol. “It is our hope that these changes will improve the condition of the patients’ cells at the time they are collected, increase the amount of vector that gets into the cells, and thus increase the amount of corrected cells the patients receive,” Kohn says.

Bluebird Bio, which plans to file for FDA approval this month, showed that its gene therapy produced normal red blood in all 35 patients who were treated in a clinical trial. It also eliminated pain episodes in all 25 of those who could be evaluated. The results appeared in The New England Journal of Medicine in December 2021. “It is quite amazing to see how quickly patients’ hemoglobin numbers come up after gene therapy,” says Mapara, a study author.

Another therapy, developed by Crispr Therapeutics in partnership with Vertex Pharmaceuticals, uses the gene-editing tool Crispr to directly alter patients’ stem cells so that they produce healthy hemoglobin. In trial results announced in June 2022, all 31 patients reported becoming free of pain crises after receiving a single dose of edited cells. The companies have filed for approval in Europe and plan to do so in the US by the end of March.

Even with such clear-cut findings, the decision to undergo gene therapy may not be an easy one for patients. Although it’s a one-time infusion, it is also a complex and lengthy process. Patients must first take a drug to release stem cells from their bone marrow, allowing them to migrate into the blood. Doctors then use a machine to remove the blood and separate out the needed stem cells, which are sent off to be modified in a lab. In the meantime, patients undergo harsh chemotherapy to eliminate their remaining stem cells and make space for the newly modified ones. Chemotherapy depletes the immune system, and can cause hair loss, fatigue, and trouble swallowing. It can also affect fertility. 

If gene therapy is eventually approved for children, it could create difficult choices for parents, since there are limited fertility preservation options for kids. “For many of our families, that’s a line in the sand for them,” said Alexis Thompson, chief of hematology at Children’s Hospital of Philadelphia, speaking at the Third International Summit on Human Genome Editing in London on March 6.

The recovery process is also long. Patients must spend about a month in the hospital while their body produces new blood cells. When they’re discharged, they can’t go back to work for about three months, Mapara says. For Junior, the lengthy hospital stay was the hardest part. “Mentally, it was a struggle,” he says. He also experienced post-chemo fogginess and memory issues. Scientists are working on drugs that could wipe out bone marrow without the side effects of chemo, but that research is in early stages.

Gene therapy also carries inherent risks. With the gene addition approach that Bluebird Bio and UCLA are using, the viral vectors tend to insert randomly in the genome, and there’s a longstanding concern that inserted genetic material could accidentally activate a nearby cancer gene, spurring disease. (Bluebird’s trial was temporarily halted by the FDA in February 2021 when two patients developed cancer, but the company determined that the cases were not related to the therapy.)

And while the curative potential of gene therapy is huge, it comes at a steep price. Last year, CSL Behring won FDA approval for a gene therapy to treat beta thalassemia, a related blood disorder. Called Hemgenix, it’s the most expensive drug in the world at $3.5 million for a one-time infusion. Other gene therapies have debuted at more than $2 million. 

In the US, about two-thirds of sickle cell patients are covered under Medicaid, the federal health insurance program for people with limited incomes. But Medicaid budgets are different from state to state and vary in what they cover. And while private insurance covers other gene therapies, patients with those plans may face high deductibles, co-pays, or other medical costs. 

If both the Bluebird Bio and Crispr therapies are approved, competition could help drive down prices. And more options may be close behind. Beam Therapeutics is enrolling patients in a trial using a more precise version of Crispr called base editing to alter blood cells. 

“In the sickle cell world, we’re very happy to see that these therapies are coming soon,” says Melissa Creary, an assistant professor of health and policy at the University of Michigan. “But even when it comes to market, it’s not going to be everywhere right away.” That’s because of the complexities of administering the therapy, which can be done only at bone marrow transplant centers. In a February financial update, Stuart Arbuckle, Vertex’s chief operating officer, said the companies plan to offer their Crispr therapy at 50 centers in the US and 25 in Europe. 

Creary, who has sickle cell, also worries that many patients may not be able to access the therapy because they can’t travel or take time off work, or don’t have financial or family support for the long recovery period.

One of gene therapy’s biggest unknowns is whether a single infusion will truly be a lifelong cure. Trials haven’t followed patients for a long enough time to show whether sickle-shaped blood cells eventually come back. Junior tries not to think about this possibility, although any hint of pain makes him anxious that a crisis may be coming on. Researchers will follow him for 15 years after his initial treatment to learn whether the therapy is still working. So far, so good.

Still, he has complicated feelings about the word cure. “I still have all the scars of sickle cell,” he says. Gene therapy didn't erase the emotional toll of living with the disease, or the bone and joint damage it had caused. That said, he hopes more people will get the same opportunity he’s had: “It would mean that they would have the right to a normal life, where nothing was off the table.”

A Gene Therapy Cure for Sickle Cell Is on the Horizon

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