First-of-Its-Kind Gene Therapy Can Be Applied to Skin Instead of Injected

Sunburns are terrible. The skin blisters and peels. Even a light brush from putting on clothes or tucking into bed sheets is agony.

Now imagine having those blisters at just six months old. But the sun isn’t the culprit; your genes are.

Thousands of people in the US have dystrophic epidermolysis bullosa (DEB), a rare genetic disorder that affects the structure and integrity of the skin and eyes. Kids with the illness are cursed with skin similar to wet tissue paper. Chronic painful blisters and wounds—sometimes inside their throats—are a part of life since birth.

The root cause is frustratingly simple: one gene mutation, which affects a critical protein that helps support skin integrity. The single genetic error makes the illness a perfect candidate for gene therapy. Yet with the skin already fragile, injections—a current standard for gene therapy—are hard to tolerate.

What about a genetic moisturizer instead?

This month, the FDA approved the first rub-on gene therapy. Similar to aloe vera for treating sunburns, the therapy comes in a gel that’s gently massaged onto blisters and wounds to help with healing. Dubbed Vyjuvek, it directly delivers healthy copies of the mutated gene onto damaged skin. An alternative version is configured into eye drops to reconstruct the eye’s delicate architecture to better support sight.

In multiple clinical trials from patients ranging from a year old to middle aged, the treatment reduced painful blisters after six months. With a massage every week, over two-thirds of the patients’ wounds completely healed, compared to just one out of five in wounds treated with a placebo. The patients’ eyesight also improved, allowing a 13-year-old volunteer to finally play Minecraft online with his teenage peers.

The therapy is the latest to expand the universe of gene therapy delivery technologies. When further developed, it won’t be limited to rare skin conditions. Because the therapy targets collagen, a critical protein that helps maintain skin structure and elasticity, the rub-on treatment could launch the next generation of moisturizers to combat fine lines and crow’s feet from aging. A subsidiary of Krystal Biotech based in Pittsburgh, which developed Vyjuvek, is already expanding into cosmetics.

It’s not all superficial. Beauty aside, the FDA nod of approval “ushers in a whole new paradigm to treat genetic diseases,” said Krystal’s CEO Krish S. Krishnan.

The Perfect Package

Vyjuvek joins a prestigious roster of approved gene therapies.

These treatments have mainly battled blood cancers and disorders. Usually, doctors need to extract immune or red blood cells from a patient’s blood. The cells are then genetically enhanced and infused back into the body. Some are amped up to pursue cancer targets. Others help boost hemoglobin in red blood cells, which carries oxygen across the body.

Unlike deeper organs, blood cells are relatively easy to access, making them a valuable resource for genetic tweaks. Just last year, one team expanded gene editing’s potential by infusing CRISPR components directly into blood, which helped brush away a toxic protein made by the liver that leads to pain, numbness, and eventually heart failure in an inherited disease.

On the surface (no pun intended), the skin is another easily accessible target—just think of the thousands of skincare products on the market. Yet our external barrier is also a formidable fortress with multiple protective layers. The top, the epidermis, is a flexible biological shield composed of tightly-knit cells, making it difficult for large intruders—including collagen—to penetrate. Current treatments for DEB rely on genetically engineered skin outside the body being grafted onto patients. It’s as intense as it sounds: patients range from a week-long stay in the hospital to a prolonged medically-induced coma to tolerate the procedure.

The team tackled the conundrum with a cleverly-balanced hand. First was deciphering the genetic error that leads to DEB: a gene called COL7A1, which encodes a type of collagen. Like anchors stabilizing skyscraper scaffolds, COL7 molecules arrange into long, thin but extremely strong bundles to hold the epidermis and the middle layer of skin together. When deficient, the two layers separate, leading to painful blisters and wounds that resemble severe sunburn or frostbite, often from birth.

Unfortunately, COL7A1 is also a tough gene to deliver due to its enormous size. The team chose their carrier “vector” carefully: HSV-1, a type of harmless herpes simple virus, extensively engineered so it doesn’t replicate inside the body or cause any disease.

The vector is the first gamble for most gene therapies. Think of them as Amazon delivery boxes. Some are extremely efficient at penetrating into cells (or into tiny mailboxes), but can only hold a small payload. Others have greater capacity, but are then dumped on your front yard—easy for others (think immune cells) to see and potentially vandalize.

Previous attempts have collected skin tissue and used viruses for cell engineering and grafting, but “correction of genetic skin diseases via direct gene transfer in vivo [inside the body] has been a longstanding yet unrealized goal in the gene therapy field,” said the team last year in a clinical study for safety.

Their final recipe worked out stunningly well. First, a healthy version of the COL7 gene was genetically packaged into the selected viral vector. The entire architecture was then suspended inside a gel, similar to molecular gastronomy, to stabilize the treatment. The end result was gene therapy inside a moisturizer bottle—a first without the need for needles or other painful procedures.

In a study with 31 patients published last December in the New England Journal of Medicine, the ointment, dubbed B-VEC, healed nearly 70 percent of painful wounds across patients, compared to just roughly 20 percent in those rubbed with a placebo. The treatment also reduced pain throughout the trial.

A New Therapy Landscape

While impressive, the treatment isn’t a cure.

Because the skin readily replaces itself with new cells that carry similar genetic defects, the gel will need to be rubbed on at least weekly by a healthcare professional. With gene therapy costing up to millions of dollars, the numbers readily stack up. But the recipients are grateful.

“With the FDA approval of Vyjuvek the DEB population has reached a monumental milestone in the treatment of this horrible disorder,” said Brett Kopelan, Executive Director of debra, an organization that supports people with the illness. “Our hopes have now been realized for a safe and effective treatment for one of the most devastating symptoms of the disorder.”

On a broader scale, the study widens the gene therapy landscape, firing the first shot at rub-on therapies—with eye drops to quickly follow.

For now, Krystal is branching out into the million-dollar skincare industry to combat aging and damaged skin. It may be tricky: unlike wounds with open skin, normal skin forms a tighter and protective barrier. But if it succeeds, the treatment may open doors to highly efficient skin care—all inside a bottle, no need for a knife.

Image Credit: liyuanalisonPixabay

Shelly Fan
Shelly Fan
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the co-founder of Vantastic Media, a media venture that explores science stories through text and video, and runs the award-winning blog Her first book, "Will AI Replace Us?" (Thames & Hudson) was published in 2019.
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