The FDA just approved rub-on gene therapy that helps “butterfly” children

Antonio Vento is 13 years old. He’s a tiny figure in bandages who doesn’t walk and, until recently, couldn’t see more than shadows. He has dystrophic epidermolysis bullosa, an inherited disease that makes his skin so fragile that kids with the illness are called “butterfly children.”

But now, thanks to a novel gene therapy squirted onto his skin and dripped into his eyes, things are better. His wounds have gotten smaller, and a visit to the eye doctor this week confirmed that his vision had dramatically improved.

“They said my right eye is 20/25,” he chirped in Spanish during a phone call. “Now I can see small things.” That includes the blocks and items in the video game Minecraft, which he has started to play.

And call him Anthony, he said. He prefers it.

On Friday, the US Food and Drug Administration approved the gene-replacement treatment Anthony received, making it the first gene therapy for sale that is applied to the outside of a patient’s body—as well as the first intended to be used on the same person repeatedly.

For “butterfly children” like Anthony, the problem is that their bodies don’t make the type of collagen that holds the skin’s layers together. The result is chronic, blistering wounds—all over the skin, but also inside the throat and sometimes on the eyes.

The treatment introduces a missing gene to skin cells so they can make collagen, and the novel delivery strategy is already being studied to treat other rare skin conditions. An inhaled gene therapy to treat cystic fibrosis is also being explored.

The treatment, called Vyjuvek, was developed by the Pittsburgh startup Krystal Biotech and is approved for treating anyone older than six months of age with this specific form of epidermolysis bullosa, a condition that until now has had few treatment options and affects only about 3,000 people in the US, according to the company.

“Since he was born, all I do is change bandages and heal wounds,” says Anthony’s mother, Yunielkys Carvajal, who emigrated to the US from Cuba in 2012 under a humanitarian visa to seek treatment for Anthony.

Since 2017, the FDA has approved five gene therapies for rare inherited diseases—Krystal’s will make it six—and several others for treating blood cancer.

But those earlier treatments are all delivered by injection or by altering immune cells outside the body. By formulating gene therapy into an ointment that’s rubbed on, Krystal has achieved what its CEO, Krish Krishnan, has called “a simple, convenient, patient-friendly way to provide the missing gene to these patients.”

The company did not say how much the treatment will cost, but other gene therapies have set record prices with the highest, for hemophilia B, coming in at $3.5 million.

Gene replacement for skin may also have lucrative future uses in cosmetics. A subsidiary established by Krystal has begun testing a version of the drug on volunteers to try to reverse crow’s feet and other wrinkles caused when people’s bodies make less collagen as they age.

That project, if it succeeds, could lead to a future where gene therapy is given to adults for non-medical enhancement, not just to treat dire health conditions. The subsidiary, named Jeune, refers to itself as a “gene-based aesthetics company.”

Really impressive

Evidence that the treatment works was presented in  a 2022 study carried out by Krystal in which Anthony was among 31 epidermolysis bullosa patients between the ages of one and 44 who had the gene-therapy ointment applied to their most severe wounds, while a placebo was put on other wounds they had for comparison. 

Caravajal, Anthony’s mother, says that during the study they picked a particularly big and painful wound on his heel. “We put it on and it went away and never opened again,” she says. “That was incredible. That was a big, chronic wound, and I’ve never seen it again. That really impressed me.”

The treatment made that wound go away, and others are shrinking, but it’s not a cure. One reason is that skin cells are constantly being replaced with new cells, which suffer from the same genetic defect. That means the therapy has to be reapplied by a nurse or doctor once a week.

Krystal says its treatment is the first gene therapy approved for such repeated use.

“I think it is really exciting, but I do worry about how durable the treatment is,” says Denitsa Milanova, founder of a Boston startup, Marble Therapeutics, which also works on gene therapy. She says collagen forms fibers in the skin that last about two or three months.

Milanova also believes the ointment only works because it’s applied to raw wounds, where the underlying layers, including skin stem cells, are exposed and can accept new genes. “But you can’t rub this on healthy skin, it wouldn’t work,” she says. That is because of how normal skin acts as a barrier, a fact which may explain why, in Krystal’s tests to combat wrinkles, its gene therapy is being injected into the skin with a needle.

Herpes virus

Scientists now have numerous tools to manipulate genes in their labs, where fixing cells in a dish or even curing mice of deadly conditions is commonplace. But the challenge in treating people is that it is harder to get corrected DNA into their bodies, a problem known as gene delivery.

Krystal is among dozens of companies seeking innovative ways to deliver replacement genes to more locations in the human body, including hard-to-reach organs like the brain.

“Delivery is the most important factor in genetic medicine,” says Maxx Chatsko, founder of Solt DB, a publisher and investment analysis company, who also buys and sells shares in biotech companies (including Krystal). “I think this could eventually be the first gene therapy people dose at home.”

Gene delivery usually involves placing a DNA strand inside a virus naturally equipped to enter a human cell and drop off the gene. In Krystal’s case, the company is using herpes simplex virus, the same one that causes cold sores.

HSV-1, as the virus is known, is very common—about half the people in the world are infected by it. That means it is fairly safe, but it also has the advantage that it naturally evades the immune system. Krishnan says that feature is what permits the drug to be used repeatedly, without causing negative reactions.

While the startup has been successful, Chatsko says there has also been some controversy over how it hit upon its strategy. In 2022, Krystal agreed to pay up to $75 million to another startup, PeriphaGen, which accused Krishnan and the company of pilfering its ideas and technology.  

Eye drops

Whether or not this is a case of a stolen “Eureka,” Krystal has already demonstrated the versatility of its approach by developing an eye-drop version of the drug at the request of Anthony’s ophthalmologist, Alfonso Sabater, director of the Corneal Innovation Lab at the University of Miami’s medical school.

“When I learned he was in the skin trial, I thought, why don’t we try that on the eye,” says Sabater, who reached a special agreement with the FDA to test the idea on a single patient, Anthony. First, Sabater surgically removed a layer of scar tissue that had built up on Anthony’s eyes. After that, he says, monthly use of the eye drops appears to have stopped those injuries from returning. 

“I think this is also the first time there’s a gene therapy for the cornea, and the first time it’s in an eye drop,” says Sabater.

It’s unclear whether or not Krystal intends to commercialize the eye-drop version of the drug.

Flight from Cuba

Anthony’s mother says the family’s encounter with cutting-edge gene technology couldn’t have been predicted when her son was born. By the time he was three, however, he had blisters on his eyes and found it difficult to swallow.

He later lost his vision, and as wounds formed on his joints, Anthony says, “it became scary to walk, so I stopped walking.”

Caravajal says she left her job at a telephone company to care for Anthony and then resolved to leave her country as well. “Cuba is a Third World country. They didn’t know the condition, and there was no medicine,” says Caravajal. “If we’d stayed in Cuba, I don’t know what would have happened.”

“I had two choices, and I chose to launch myself into the unknown,” she says.

Anthony’s father, Antonio Vento, holds a Spanish passport, so he was able to fly to the US and secure a humanitarian visa for Anthony and his mother. She remembers the date they arrived: the 16th of December, 2012.

The family first tried to get acclimated and sought out a team of doctors to help Anthony. But his mother was ready to try for more. “It’s a degenerative disease. It’s not something you can go to the pharmacy for, but you don’t want to sit with your arms crossed, either,” she says.

Anthony was first enrolled in a clinical trial in California with a company called Fibrocell. That treatment had no effect, but Caravajal says that’s when she met Suma Krishnan, president of Krystal (she and Krystal’s CEO are married), who encouraged her to enroll Anthony in the study of the gene-therapy ointment.

The results have been impressive. “It’s not a definitive cure, but it’s the best I have seen with his wounds. Every time we see the doctor we take pictures, and his injuries are smaller now, and some are gone,” says Caravajal

The family has remained part of the clinical study, which has continued in an open phase that allows the volunteers to keep accessing the drug. Each visit, they get to use eight small ampules of the gene cream, and they can decide where on Anthony’s body to put it.  

What happens next, when the drug needs to be purchased, is an open question for the family.

“We tell them that we need this medicine, and we don’t want it to stop,” says Caravajal. “If it were possible, we’d use more.”