A landmark gene-editing treatment for sickle cell disease moves closer to reality

The Food and Drug Administration may soon approve a therapy that uses the gene-editing technique called CRISPR to treat sickle cell disease. It would mark the first time gene editing moves from the lab into clinical use.

A committee of advisers to the FDA meets Tuesday to review the scientific evidence for the treatment, including whether sufficient research has been done to assess its long-term safety. The agency has until Dec. 8 to make a decision about the therapy, known as "exa-cel."

In an analysis posted by the FDA Friday, agency scientists conclude exa-cel is highly effective at preventing episodes of excruciating pain that plague sickle cell disease patients. The treatment worked in 29 of 30 patients followed for at least 18 months and doesn't appear to cause any serious short-term safety concerns, the FDA concluded.

However, the FDA scientists raised concerns about whether sufficient research had been done to spot "off-target" effects of the treatment — unintended editing errors that missed their mark in the DNA and that could potentially cause long-term health problems.

Because of the high stakes of approving an entirely new kind of technology to treat people for the first time, the FDA plans to focus the advisory committee's discussion about the long-term safety of gene editing and whether additional analyses are needed.

First patient says the treatment changed her life

The committee will hear presentations from Vertex Pharmaceuticals Inc., the Boston company that led the development of exa-cel along with nearby CRISPR Therapeutics. FDA scientists and independent researchers will also brief the committee.

During the public comment portion of the meeting, the committee will also hear from Victoria Gray, a Mississippi woman who in 2019 was the first sickle cell patient to receive the treatment as part of the clinical trial that was conducted by Vertex to win FDA approval. NPR has chronicled Gray's experience.

"I think they should approve this treatment," Gray told NPR in her most recent interview. "It's really life-changing."

The treatment would be the first of what researchers hope will be many new medical treatments that use CRISPR. The gene-editing technology allows scientists to easily make precise changes in DNA. Researchers are studying CRISPR-based therapies for conditions including muscular dystrophy, diabetes, cancer, Alzheimer's, AIDS and heart disease.

"It's extraordinary to think that we're on the verge of an approval of the first CRISPR therapy," says Jennifer Doudna of the University of California, Berkeley, who shared a Nobel Prize for her role in discovering the technique.

"As a scientist, I think we always hope that our work will affect people in a positive way — and this is one of those moments," Doudna says. "It's kind of a landmark moment for the technology, industry and hopefully the people who will benefit from it."

A genetic illness that afflicts millions

Sickle cell disease is caused by a genetic defect that produces an abnormal form of the protein hemoglobin, which red blood cells need to carry oxygen through the body. These red blood cells become misshapen and get jammed inside blood vessels.

The jagged cells cause unpredictable attacks of intense pain and damage vital organs. Throughout their lives, sickle cell patients are repeatedly rushed to the hospital for powerful pain drugs and blood transfusions. They often can't finish school, hold jobs or care for themselves or their families. They're also prone to strokes and other serious complications. Patients usually die about 20 years prematurely.

The disease disproportionately occurs among people of African, Middle Eastern and Indian descent, affecting millions around the world and about 100,000 in the U.S. Although a rare disease, sickle cell is one of the most common genetic disorders. About 20,000 patients in the U.S. have the severe form of the disease the CRISPR treatment would initially be used to treat.

For the treatment, doctors remove cells from each patient's bone marrow, edit a gene with CRISPR and then infuse billions of the modified cells back into patients. The edited cells produce a form of hemoglobin known as fetal hemoglobin, restoring normal red blood cell function. While not a cure for the disease, the hope is exa-cel will be a one-time treatment that will alleviate symptoms for a lifetime.

In a study involving 30 patients, the treatment resolved the severe pain crises for at least 18 months for 29 of the subjects — 96.7%. That transformed the lives of Gray and the other patients, enabling them to work, go to school and care for themselves and their families. The treatment has also produced similar results for patients suffering from a related condition known as beta thalassemia.

"These results are incredible," says Dr. Haydar Frangoul, director of pediatric hematology, oncology and cellular therapy at the Sarah Cannon Research Institute in Nashville, Tenn., who led the study. "They are truly transformative."

Other independent experts agree.

"The amount of change in peoples' lives is super encouraging," says Dr. Lewis Hsu, a professor of pediatric hematology at the University of Illinois Chicago and chief medical director of the Sickle Cell Disease Association of America. "It's very significant."

Cost and complexity are likely barriers

One concern, however, is the likely cost of the therapy, which could be as much as $2 million per patient. The treatment is also complex, requiring a bone marrow transplant and lengthy hospitalization. Those factors may put it out of reach for those who need it most in the U.S., as well as in less affluent countries where the disease is most common.

"I'm worried that this will be a very highly lauded technology that people will not be able to use," says Melissa Creary, an assistant professor at the University of Michigan School of Public Health who studies sickle cell. "I think the people who need this therapy the most will not be able to afford it."

Many of the countries where most sickle cells patients live don't have enough sophisticated medical centers to provide the complicated treatment, Creary notes.

"I have to ask the question: How many people are going to be able to actually benefit from the technology?" Creary says.

Vertex officials say the company is working with Medicaid and private insurance companies to pay for the treatment and developing other ways to make the treatment accessible.

University of Illinois Chicago's Hsu argues that while the price is high, it's still cost-effective given how much it costs to care for sickle cell patients their entire lives.

"There is a return on investment to the health care system," he says. "These cost savings would make it worthwhile for those upfront costs."

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