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FDA expected to approve first CRISPR gene-editing treatment, bringing hope to thousands with sickle cell disease


By Meg Tirrell, CNN

(CNN) — Before Johnny Lubin got a potentially life-changing experimental treatment at the age of 13, he recalls, he had one main concern.

“I was worrying that I might get, like, superpowers,” said Johnny, now 15, who lives in Trumbull, Connecticut, about 60 miles north of New York City.

One of an estimated 100,000 people in the US with sickle cell disease, Johnny was also one of the first in the world to try a new kind of medicine: one that uses a gene-editing tool called CRISPR to offer a potential cure.

That treatment, known as exa-cel and made by Vertex Pharmaceuticals and Crispr Therapeutics, is expected to be approved by the US Food and Drug Administration today.

For many in the sickle cell community, it’s been a long time coming. The disease predominantly affects African Americans, afflicting an estimated 1 of every 365 Black babies born, according to the US Centers for Disease Control and Prevention, and has long been considered neglected by the pharmaceutical industry. About 20,000 people in the US are thought to have a severe enough form of the disease to potentially qualify for a treatment like this.

The first ‘molecular disease’

The underpinnings of sickle cell have been understood for almost three-quarters of a century; in 1949, chemist Linus Pauling published a paper in the journal Science describing how the oxygen-carrying protein hemoglobin is different in people with sickle cell, declaring the malady the first “molecular disease.” That was four years before the famous double-helical structure of DNA was proposed.

“We’ve kind of been waiting for this ever since DNA was first discovered,” said Dr. Lewis Hsu, chief medical officer for the Sickle Cell Disease Association of America and a physician who treats kids with sickle cell. “It’s been a long, long time coming.”

Sickle cell is caused by a genetic mutation that leads red blood cells, which contain hemoglobin and ferry oxygen around the body, to be misshapen, like crescents or sickles. These misshapen cells can get stuck in vessels, causing organ damage and – a hallmark of sickle cell – horrible bouts of pain that can last days, called pain crises.

“It was kind of hard for me to do things like have fun and stuff, because I’d always have to be worried about if I’d have a pain crisis,” Johnny said. The pain “would mostly be in my lower back, and it would always be like a pounding pain. … It hurt a lot.”

Until now, the only hope for a cure for people with sickle cell was with a bone marrow, or stem cell, transplant. But Johnny, like more than 80% of patients with sickle cell, couldn’t find a donor that matched.

For the first 13 years of his life, Johnny was hospitalized every few months because of pain crises and other complications from the disease. His parents had to stock opioid pain medicines and always had a “go bag” with them in case they needed to go to the hospital on short notice.

But since October 2021, when Johnny received a one-time infusion of his own gene-edited cells, he hasn’t had another crisis.

“He’s been like a normal child,” said Johnny’s mother, Fabienne Desir. “It’s life-changing for us.”

A new tool for editing genes

CRISPR is a gene editing technique that enables scientists to make precise cuts in DNA. The first scientific paper about it was published in 2012, and its development – by Jennifer Doudna and Emmanuelle Charpentier – won the Nobel Prize in chemistry just eight years later.

For sickle cell, patients’ cells are removed from the body and CRISPR is used to make an edit that turns back on production of fetal hemoglobin, a form of the protein that babies make in the womb. Once the edited cells are returned, the fetal hemoglobin can make up for the mutated hemoglobin that causes sickle cell, explained Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center, who helped run the trial Johnny participated in.

“Fetal hemoglobin, we know, has a higher oxygen-carrying capacity than adult hemoglobin or sickle hemoglobin,” Bhatia said.

Making fetal hemoglobin along with sickle hemoglobin renders a patient similar to someone with sickle cell trait, Bhatia explained; that’s when someone inherits one sickle cell gene and one normal gene, and they “do not have any of the complications of the disease,” she said. “It is more than good enough.”

Indeed, Dr. David Altshuler, chief scientific officer at drugmaker Vertex, pointed out that some people naturally have genetic mutations that keep fetal hemoglobin high, “and they don’t have symptoms, even if they have the disease.”

“So it was like a physiologic, demonstrated approach that would work if you could turn on fetal [hemoglobin],” he said.

Clinical trial results, including Johnny’s, bear that out. In data cited by the FDA ahead of an advisory committee meeting on the therapy in October, 29 of 30 patients reached the trial’s main goal: freedom from a pain crisis for at least 12 months after treatment. The longest time without a crisis was 45.5 months, almost four years, and researchers will continue to follow the patients.

The hope is that the effects could last their entire lives.

“We don’t have as much long-term data as we do for stem cell transplant,” Bhatia said. “But that would be the hope, is that this would be comparable to a transplant and it would be sustained.”

The CRISPR treatment, which is called Casgevy in other countries where it’s already been approved, isn’t the only one on the near-term horizon for sickle cell; another, using a different technology, is only weeks behind, with a potential approval by December 20.

Made by bluebird bio, the second approach involves an older technology, using a virus to deliver a healthy copy of the gene that produces adult hemoglobin to make up for the one producing the sickled form. It also involves removing the patient’s cells from their body, and then returning them. It’s shown similarly encouraging results.

“These both bring tremendous benefit to the patients,” bluebird CEO Andrew Obenshain said.

A million-dollar-plus price tag

Whether people will be able to afford and access these treatments, though, is a key question. One-time genetic treatments typically carry price tags of upwards of $1 million each and require the infrastructure of large medical systems.

“I don’t know whether it will get covered and paid for,” Hsu said. And the types of academic medical centers that could offer the treatment are typically in larger cities, he noted.

“I’m in Illinois, and they’re basically concentrated in Chicago, which leaves the entire rest of the state kind of bare, and so people would have to travel a very long distance to be able to get to this,” he said. “And then some states, there just isn’t anything.”

And the treatment isn’t simple; it requires a lot of additional care around it that adds to the cost. Patients typically stay in the hospital for about a month to prepare for the re-infusion of gene-edited cells, first going through what’s known as “conditioning”: several days of chemotherapy to wipe out their bone marrow, which makes blood cells and platelets, so they’re ready to receive the new cells.

Then, “it takes a period of time for those cells to kind of take up residence in the bone marrow and grow,” Bhatia said.

That period around the infusion can be very difficult for patients and their families; Johnny’s mom described how Johnny’s “whole GI tract was inflamed; he couldn’t swallow. That was really painful. It was hard to watch.”

And that chemotherapy conditioning carries risks, including the possibility of infertility, Hsu noted. He pointed out there are methods of trying to preserve fertility before the treatment, but coverage for that can vary by state as well. And more than half of people with sickle cell in the US depend on Medicaid for their primary insurance, according to the advocacy organization Sick Cells.

The conditioning treatment also carries a potential risk of cancer; two patients in earlier stages of bluebird’s trial died after developing leukemia, which was found unlikely to be related to the gene therapy itself but potentially from the chemotherapy needed to prepare for it.

Vertex’s Altshuler said his company is working on improving the conditioning process to make it gentler, to “create the opportunity for the new cells to go in without any other damage to the body,” although he noted that it’s still in the research phase.

Scientists also are vigilant about potential off-target effects of the CRISPR gene-editing approach – meaning DNA could be cut in an unintended place – and the FDA convened a full-day meeting in October to assess those risks. Many experts there expressed confidence that those risks were “relatively small.”

To Altshuler, the bigger deal in a potential approval of exa-cel is that there’s such an advancement for sickle cell disease, not that it’s the first CRISPR therapy.

“We’re not about a tool; we’re about the disease,” Altshuler said. “Once we found the way in, and now we’ve shown you can treat this disease very effectively if you can increase fetal [hemoglobin], we’re going to drive on that.”

The company is in the very early stages of researching how to achieve an increase in fetal hemoglobin using a pill, so patients wouldn’t need to go through the conditioning and gene editing process, Altshuler said.

He noted that it’s very early days but said that kind of approach could be the answer to the “very valid” question of “how are we going to help people around the world with this therapy?”

The majority of patients with sickle cell live in Africa and India, and bluebird’s Obenshain said the company doesn’t have plans to introduce “this version” of its gene therapy there, noting that it’s too expensive to manufacture.

“Basically, for every patient, we manufacture one drug lot,” Obenshain said.

For Johnny and his family, the effects of his treatment have been so transformative they now celebrate the day he got the infusion of gene-edited cells as his second birthday. He can go swimming – previously an activity guaranteed to trigger a pain crisis – without fear and spent all of last summer in the pool, his family says.

And although he didn’t gain the superpowers he worried about, he got something potentially even better: the chance to be a normal kid.

“I’m starting to teach him how to drive,” said Johnny’s dad, JR Lubin. “So we’re stepping into the regular worry of, you know, raising a teenager.”

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