The FDA just approved the first gene-editing treatment, and CHOP played a key role

Segun Fadeyi was in near-constant anguish from the painful condition called sickle cell disease. Several times a year, it got so bad that he went to the hospital, with pain he likened to having his bones crushed.

No longer. Two years ago at Children’s Hospital of Philadelphia, the Canonsburg, Pa., resident underwent an experimental gene-editing treatment called CRISPR. Physicians are wary of using the word cure, but all indications suggest he is free of the disease.

“I haven’t had any pain whatsoever,” he said. “It’s a second lease on life.”

With FDA approval of the cutting-edge therapy announced Friday, more patients will soon be able to get it — provided their insurers are willing to pay a list price that could approach $2 million.

Called Casgevy, it is the first approved treatment that involves editing a person’s genes, a remarkably fast turnaround for a technique invented barely a decade ago.

The FDA has approved other forms of gene therapy — the umbrella term for any gene-based method to correct a deficiency in a person’s DNA — starting in 2017 with two treatments that were developed in Philadelphia. But those techniques do not allow physicians to make “edits” at a specific point in a patient’s DNA, among other limitations.

The CRISPR method, by contrast, is the biological equivalent of the control-F command on a personal computer, said CHOP physician Stephan A. Grupp, who chaired the steering committee for the sickle cell study.

“It goes to one place and makes that one cut,” he said.

Sickle cell disease is named for the curved shape of patients’ red blood cells, caused by an abnormal form of hemoglobin inside those cells. The CRISPR editing disables one gene, thereby “turning on” another, allowing patients to make a normal form of hemoglobin. The pain subsides or goes away. The treatment also appears to reduce the risk of strokes, anemia, and organ dysfunction.

Such pinpoint editing could pave the way to treating other genetic diseases. University of Pennsylvania researchers are helping to study an approach for preventing a type of heart disease. Scientists at ChristianaCare in Delaware are testing CRISPR against cancer. A team at Penn and CHOP won a $26 million grant earlier this year to study CRISPR for treating three rare metabolic conditions.

Yet those treatments likely are years away. Sickle cell disease was a special case, with unique characteristics that made it the perfect candidate for CRISPR.

Patient advocates are hailing the new therapy for a condition that disproportionately affects Black people, saying it has historically been underfunded and undertreated due to systemic racism. Many patients have reported difficulty in getting doctors and nurses to take their symptoms seriously.

Fadeyi, 33, who is Black, said he was reluctant to ask his physicians for pain medications, worried that they would think he was addicted to opioids and exaggerating his pain symptoms in order to get a prescription.

Now the pain is just a bad memory.

“I have to remind myself,” he said. “Sometimes it’s hard to believe.”

Pronounced “crisper,” the new therapy’s name is an abbreviation for a scientific tongue-twister: a stretch of genetic code called “clustered regularly interspaced short palindromic repeats.”

The technology has one of the wackier origin stories in modern medicine. While performing quality-control tests on bacteria used to make yogurt, scientists discovered that the microbes had a rudimentary type of immune system: an ability to “recognize” the genetic fingerprints of invading viruses. (Bacteria can be infected by viruses, just like we can.)

Other scientists discovered they could repurpose this bacterial tool to search for stretches of genetic code of other organisms, including people. What’s more, they learned how to add on an editing feature: an enzyme that cuts the targeted DNA in a precise location.

Two of the technology’s pioneers, Emmanuelle Charpentier and Jennifer Doudna, were awarded the Nobel Prize in chemistry in 2020.

CRISPR is now widely used by scientists for the study of lab animals. It is even available in mail-order kits, allowing amateurs to make small modifications in bacteria.

Using CRISPR to treat disease in humans is a bigger challenge. Among other hurdles, the editing still is not 100% precise, said Eric B. Kmiec, executive director of the ChristianaCare Gene Editing Institute in Delaware. Scientists also are still figuring out how to deliver such therapies to the right part of the body.

That’s why sickle cell disease was an ideal first candidate. Physicians realized they could remove stem cells from a patient’s bone marrow, carefully edit and test them outside the body, then put them back in — in effect, a bone-marrow transplant in which patients are their own donors.

In Casgevy, the CRISPR “recognition” tool is stored in stretches of the genetic molecule RNA. (It’s a different type of RNA from what’s used in the Pfizer and Moderna COVID-19 vaccines.)

The way it works is rooted in a phenomenon that occurs during pregnancy, said Kiran Musunuru, a professor of cardiovascular medicine and genetics at Penn’s Perelman School of Medicine.

Fetuses make a type of hemoglobin that binds more strongly to oxygen than the adult form. That gives the fetus “first dibs” on available oxygen during pregnancy, he said.

Soon after birth, a gene directs infants’ bodies to scale back on the production of that fetal hemoglobin, while another gene directs them to start making the adult form. But in people with sickle cell disease, a mutation in that second gene causes their adult hemoglobin to stick together and form crystals, causing their red blood cells to curve into the telltale sickle shape.

That’s where Casgevy comes in. It uses CRISPR to disable the gene that shuts down the production of fetal hemoglobin, allowing adults once again to make the healthy form of hemoglobin that sustained them as fetuses, Musunuru said.

“It’s almost like a double negative,” he said.

The CRISPR treatment for sickle cell is still a long, expensive ordeal.

Patients must have blood stem cells harvested from their bone marrow for editing, then they undergo chemotherapy to make space for the edited cells to be reinfused into the body. Afterward, they spend more than a month recovering in the hospital.

Underinsured patients may have trouble getting access to the new drug, made by Switzerland-based CRISPR Therapeutics and Boston-based Vertex Pharmaceuticals.

Some patients will have to travel for the treatment, as it is expected to be available only at medical centers with the necessary expertise. If they are insured by Medicaid, the publicly funded insurer for low-income families, they may have trouble getting coverage authorized for treatment in another state, said Grupp, who oversaw the treatment of Fadeyi and half a dozen other study participants at CHOP.

At CHOP, physicians are committed to fighting insurers over any coverage denials, he said. As with other expensive, one-time therapies that have recently come on the market, proponents argue that the large up-front price is worth the avoidance of a lifetime of medical bills.

Treating other diseases with CRISPR is likely years away.

At ChristianaCare, Kmiec is studying the use of CRISPR to fight cancer, editing away the genetic defenses inside tumors so they are more vulnerable to traditional treatments such as chemotherapy.

Musunuru, the Penn physician, cofounded a biotech firm that’s testing a CRISPR-based treatment on people with very high levels of cholesterol.

Both of those approaches involve making edits directly inside the person’s body. Early results are promising. But FDA regulators have said that with such inside-the-body editing treatments, they are concerned about the risk of “off-target” effects — the possibility that edits get made in other parts of the genome, beyond the targeted spot.

Regulators also raised that issue in reviewing the sickle cell treatment. But Grupp and other physicians involved with the trial say there was no evidence of unwanted edits.

Fadeyi says his life was transformed by the infusion with his edited stem cells more than two years ago at CHOP.

He goes to his job every day as a district manager for a grocery chain, free of worry that he might suddenly have to rush to the hospital. And he is confident he will be around to raise his son, Elliot, who was born in June 2022, just a few months after his father completed the treatment.

Doctors have told him that as far as they can determine, his CRISPR-edited stem cells will persist for the rest of his life.

“Knowing I’ll be there for the long term, it is life-changing,” he said. “It was one and done. I don’t have to do it again.”