This gene-editing therapy could cure sickle cell disease, and it’s close to FDA approval

A breakthrough treatment for sickle cell patients could soon become the first gene-editing treatment to be approved by the Food and Drug Administration (FDA). 

Sickle cell disease (SCD) is an inherited blood disorder that affects roughly 100,000 Americans, most of whom are Black. The disease causes red blood cells to become sickle or c-shaped, clumping together and clogging blood vessels, causing pain and other complications. 

There is only one approved treatment that can cure sickle cell disease: a bone marrow transplant in which a healthy donor offers stem cells that create red blood cells in the sick patient. In the vast majority of cases, the best donor is the patient’s fully related sibling, but even then, a sibling only has a 1 in 4 chance of being a match. 

“Only about 18 percent, or less than 1 in 5 individuals, will have a suitable match. And the best match possible is a sibling who happens to have the same tissue type that they do, but only about less than 20 percent of sickle cell patients will have a sibling with an appropriate match,” said Alexis Thompson, chief of the Division of Hematology at Children’s Hospital of Philadelphia. 

As a result, doctors and regulators are highly interested in a new treatment known as exagamglogene autotemcel (exa-cel), which was developed through a partnership between Vertex Pharmaceuticals and CRISPR Therapeutics.

This treatment takes a patient’s stem cells and edits them to produce more fetal hemoglobin, an abundance of which has been observed to cause red blood cells to not “sickle.” 

“Gene therapy really becomes a really important option because the patient is their own donor,” said Thompson. 

The idea of altering a person’s genes to potentially cure a disease sounds like science fiction, but gene therapy has been used more and more in medicine in recent years. More than 30 FDA-approved gene therapies are used to treat illnesses like cancers, hemophilia and certain degenerative disorders. 

The FDA approved a gene therapy for thalassemia, an inherited illness similar to SCD, last year. Exa-cel is also indicated for this disease. 

According to physicians, even with the addition of next-generation technology, the use of exa-cel is not too far off from what SCD transplant recipients already experience. 

“Though they’re doing something novel in the space of fixing the problem in the cell, you’re still giving a transplant because you need to get those cells back in the body,” said Titilope Fasipe, co-director of the Texas Children’s Hospital sickle cell program. 

“If you know anything about transplant, it’s not an easy therapy. It’s a therapy that requires intense medications and monitoring in the hospital. And then intense monitoring even after the transplant, but the goal is to cure the disease,” Fasipe added. 

Before a patient can receive new bone marrow, they must first undergo chemotherapy to kill off the faulty cells. The same is done for patients undergoing exa-cel gene therapy. 

Those who have undergone the gene therapy say the process was life-changing for them. 

Victoria Gray, the first sickle cell patient to undergo exa-cel, told the FDA’s advisory committee on cellular, tissue, and gene therapies that the treatment freed her from constant hospital visits due to SCD-related pain events. 

“Before this treatment, my entire childhood and adult life was plagued with severe pain, fatigue, numerous hospital stays and the fear of dying,” Gray said.  

“After receiving this treatment, I no longer have pain and I no longer have to take opioids. I no longer have hospital stays or receive blood transfusions,” she said. “I get to participate with my kids and join them in their activities, when they play sports, cheer them on at their dance events and just be here and just to play with them, knowing that I no longer have to leave them to go to the hospital.” 

There are still concerns, though, particularly regarding the use of CRISPR technology and the potential for off-target editing or unintentional genetic alterations. 

Daniel Bauer, associate professor of pediatrics at Harvard Medical School and director of the gene therapy program at Boston Children’s Hospital, addressed these concerns to the FDA gene therapy committee last week. 

Speaking on the potential hazards of off-target gene editing, Bauer said, “My guess is it’s a relatively small risk in the scheme of this risk-benefit, but it’s new and unknown but easily measurable.” 

When asked if the risk could be “catastrophic,” Bauer acknowledged that given the millions of cells that are used in the process, there’s always a risk that one cell could mutate and cause leukemia. 

“Has it been shown that an off-target effect of gene editing causes leukemia? No. Theoretically, could it? Yes,” said Bauer. 

This concern has followed CRISPR throughout its history. According to Thompson, some off-target edits can be inconsequential, having no major effect whatsoever, but the possibility of inducing a malignancy is ever-present. 

“There has been extraordinary effort put by not just by the sponsor but by people across the field to look for ways to mitigate or to reduce, or what some people call to de-risk CRISPR casts,” said Thompson. 

Following the presentations from researchers last week, some of the FDA committee members concluded the potential benefits offered by exa-cel outweighed the risks, though others said they felt further study was warranted. 

But as is the case with new medical advancements, not all those who can benefit will get to take part. According to the Sickle Cell Disease Association of America, the cost of exa-cel is estimated to be upwards of $2 million. 

“My double-edged sword about all of this, about gene therapy, is that access is still going to be the biggest barrier,” Fasipe said. “I can stand outside on the street tomorrow and say, ‘Hey, I have a great treatment for sickle cell,’ and I will tell you I will not reach everybody with sickle cell disease. And that’s because the majority of people, especially adults with sickle cell disease, do not have access to comprehensive care by an expert who manages sickle cell disease.”

This advancement, however, still provides a degree of hope for the future of treating SCD and providing more people with a chance at living without the pain brought on by the disease.

Recalling a clinic visit with a few 3-year-old patients of hers, Fasipe said being able to talk about a better future for them gave her joy. 

“I’m already happy on their behalf and what I tell families of children that young is that because the future is now, their child will get some version of a better tomorrow for sickle cell disease,” said Fasipe.  

“If we fast forward in five years, I’m sure the technology will continue to advance, more options will be available. So, for a child in today’s world with sickle cell disease, living in the United States, there’s a lot of hope that even if they don’t get gene therapy in 2024, there is a more of a reality for them to get it sometime in their new future when they’re still a child.” 

A decision on the approval of exa-cel is expected by Dec. 8.