FDA approves gene therapy for sickle cell disease: 'One incredible journey of success.'

Federal officials Friday approved two gene therapy treatments for sickle cell disease, welcome news for tens of thousands with the inherited blood disorder that causes terrible pain crises and early death.

Sickle cell is the most common disease to receive approval for gene therapy treatment, following decades of development and years of approvals for therapy for people with rarer conditions.

The therapies will be extremely expensive and limited at first to patients 12 and older who have the most severe form of the disease, predicted to be about 20,000 of the 100,000 Americans who suffer from sickle cell disease.

But the Food and Drug Adminstration approval offers a viable option for thousands of people whose lives have been dominated by frequent, unpredictable lightning strikes of searing pain. People like Jennelle Stephenson of Cleveland, Tennessee.

Now 33, Stephenson was one of the first to receive sickle cell gene therapy in a clinical trial six years ago.

Before the treatment, Stephenson lived her life on a razor's edge.

Every flight of stairs she climbed might trigger a pain crisis requiring a dayslong hospital stay. The misshapen blood cells that clogged her vessels could also cause unseen organ damage or even trigger a debilitating stroke.

For two years after receiving her gene therapy treatment, she couldn't quite believe she didn't need to worry about such pain crises.

"The shadows or remnants are there, waiting to come out ‒ but it never happened," she said. "For 27 years, I lived one way and all of a sudden I had to retrain my mind and body to live (a different) way."

Although not enough time has passed to declare the patients "cured" of their sickle cell disease, after gene therapy, 95% of recipients, like Stephenson, are symptom-free.

"It's been one incredible journey of success for me," she said.

What is sickle cell disease?

Sickle cell disease – often called sickle cell anemia, which is its most serious form – is caused by a genetic disorder that alters the ability of red blood cells to deliver oxygen to every part of the body.

Normal daily activities such as climbing stairs, running laps in elementary school gym class or roughhousing with friends can trigger a pain crisis because the sickled red blood cells can't carry oxygen efficiently.

Victoria Gray, another early recipient of gene therapy, described the pain starting in an arm or leg and ricocheting across her body, feeling like a surge of lightning.

Meditation, hot towels, massages and even powerful medications barely touched the agony that took Gray's breath away and often left her unable to walk or even lift her arms.

Gray, of Forest, Mississippi, had her first sickle cell pain crisis when she was 3 months old. Every year of her childhood and young adulthood she spent more and more time in hospitals.

She knew no one else with sickle cell disease, but while still in elementary school, she read everything she could about it.

"It left me in a lonely place," she said recently on a recent Zoom call with reporters. "All I learned was I was doomed to die."

In the U.S., the disease typically kills people by the time they reach their early 50s. In sub-Saharan Africa and India, where medications and blood transfusions can be difficult or impossible to access, sickle cell disease often ends lives in childhood.

Sickle cell research has been underfunded and patients are often disregarded and mistreated because they are people of color, said Dr. Sharl Azar, medical director of the Comprehensive Sickle Cell Disease Treatment Center at Massachusetts General Hospital in Boston.

Both Gray and Stephenson said they have to advocate for themselves to get basic medical attention. They make an effort to put on makeup and brush their hair as they're rushing to the hospital in the middle of the night, desperate for pain relief.

Azar said he has a patient of color who puts on her college sweatshirt and another who brings along his wife, who is white, so he'll get more attention and less skepticism when he asks for heavy-duty pain medication.

"When our patients come to the emergency room, they are frequently treated like criminals," Azar said. "I've had patients tell me they'd rather bite on a shoe at home than come into the ER and lose their dignity."

Choosing gene therapy

Gray was in and out of hospitals seven times during each of the two years before her gene therapy.

Then 32, she explained to her doctor that she was too tired to go on. "I told him I couldn't live like this anymore."

She considered getting a bone marrow transplant ‒ the only other treatment that is considered to provide long-term relief from the pain crises and damage of sickle cell disease.

But only about 15% of patients have siblings who are a good match to donate the bone marrow needed for a transplant, and even then there's a risk it might not work.

Stephenson, who also considered the procedure, has three older siblings, but none was a match. Gray's brother offered a half-match. His marrow would have left her vulnerable to something called graft-versus-host-disease, which meant she'd need to be on immunosuppressive drugs for a year.

Although Gray had been mistreated by other doctors, Dr. Haydar Frangoul, who runs the pediatric hematology and oncology program at the Sarah Cannon Research Institute in Nashville treated her with dignity and concern. When he offered her a spot in his gene therapy trial, Gray agreed.

"I was trading sickle cell for something unknown," Gray said.

Despite its promise, gene therapy remains an ordeal.

For both Gray and Stephenson, the process took about a year. First doctors remove bone marrow cells, which are responsible for manufacturing red blood cells. Over about three to six months, laboratory scientists tinker with those cells so they'll produce many more healthy red blood cells and almost no sickled ones.

As with a bone marrow transplant, the patient then has to undergo a round of chemotherapy to kill off their old, sick cells and make room for the new ones. This typically makes a person infertile and temporarily destroys the immune system, so they have to stay in the hospital for about five weeks.

Gray had mouth sores, lost her hair and was very weak after her chemo.

Cells that have been manipulated in the lab are then infused back into the patients. Because the cells are their own, there's no chance of the type of rejection that can happen with a bone marrow transplant. In nearly all patients in the clinical trials, the modified cells successfully took hold, replacing the unhealthy ones.

However, patients have to be monitored for some time after the procedure to make sure it works, staying close to the hospital for testing.

While there are systems set up for cancer patients who have to undergo long procedures and follow-ups and their family members who want to be near them, no such programs exist yet for sickle cell patients, Azar said.

Gray didn't worry about the loss of fertility because she already had three children when she received her gene therapy five years ago.

Stephenson said she chose not to worry about the long-term effects of her disease or the chemotherapy.

"I decided to deal with today's problems today and tomorrow's problems tomorrow," she said. "As they arise in my life, I'll tackle them."

Price of transforming lives

It's not yet clear how many patients will sign up for gene therapy or who is best suited for the treatment.

Some will depend on the price set for the treatment and whether government and private insurance will cover the cost and those extras, like housing while being monitored. Gene therapy for other, rarer conditions has been priced as high as $3.5 million.

There are two different approaches, both approved Friday. One, called Casgevy, from Vertex and CRISPR Therapeutics, is the first to use the CRISPR gene editing technology, which won a Nobel prize in 2020. It is being offered for $2.2 million. The second, called Lyfgenia, comes from bluebird bio and uses a slightly different technology to accomplish the same goal. It is priced at $3.1 million.

Azar doesn't have a preference between the two yet. He doesn't know which of his sickle cell patients would be the best fit for gene therapy. He wants a patient or two to get it, to see who fares best: whether those who are struggling the most with their disease, who are getting the least benefit from existing treatment or who are still young and healthy.

Gene therapy can prevent future damage to the body, but it cannot reverse the problems already created by the disease, which is why it's important to treat patients while they're young, said Frangoul, who also works at HCA Healthcare’s The Children’s Hospital At TriStar Centennial. He's currently testing the treatment in children as young as 5 and may eventually begin offering to kids even younger.

"Sickle cell disease is like a hammer hitting a wall," he said, causing a ding in the wall. "I can take away the hammer. I cannot fix the wall."

Dr. Stuart Orkin, at Boston Children's Hospital, hopes what's been learned from gene therapy can be used to develop effective treatments that are less challenging and expensive, so they can be provided to more sickle cell patients in the U.S. and across the world.

Several researchers are working on ways to deliver gene therapy with less toxic drugs than chemotherapy or to do all the genetic tinkering inside the body, removing the need for fancy laboratories and expertise.

Orkin said he hopes to develop a pill that can accomplish most of the same benefits, though he doesn't yet know if it's possible. He spoke with reporters on a call Tuesday organized by the Doris Duke Foundation, which funded some of his early work on sickle cell gene therapy.

Azar said, if nothing else, gene therapy has raised public awareness about sickle cell disease.

"It's allowing sickle cell to come to the social consciousness," he said. "That's a huge boon to the community."

Stephenson said she hasn't had a single pain crisis or hospitalization in the six years since her gene therapy treatment. She was able to finish school and now works as a behavior analyst, helping many on the autism spectrum.

"Living the life I've had and going through what I went through, my career choice lines up," she said, adding that her job brings her joy. "I do my best to give my kiddos what they deserve in terms of patience, empathy and a tailored program to meet them where they're at."

Gray is now 38 and finally able to work full-time after finishing a clinical nursing degree. Wanting to offer hope to others the way her treatment provided her, she became an advocate for gene therapy and other less expensive, more accessible sickle cell treatments.

Tapering off three high-dose pain medications was tough, but "after that, my life has really been transformed," she said. "I get to live life as a normal person."

One morning about eight months after her treatment, Gray woke up and thought her whole body had gone numb because she didn't feel any pain. She started pinching her face and thighs before realizing that the absence of pain was proof her treatment was working.

"I can dream again," she said. "I had stopped dreaming and hoping for anything. Now I have big dreams and big plans."

Karen Weintraub can be reached at kweintraub@usatoday.com.

This article originally appeared on USA TODAY: Sickle cell gene therapy approved by FDA. How it could change lives.