Topical Gene Therapy FDA-Approved for Severe Skin Disease, Dystrophic Epidermolysis Bullosa

The newest FDA-approved gene therapy treats the severe, skin-peeling condition dystrophic epidermolysis bullosa (DEB). The gene treatment has been a long time coming, but it differs from the handful of other approved gene therapies: it isn’t a one-and-done.

My now decade-old book The Forever Fix: Gene Therapy and the Boy who Saved It, told the stories of children who had received one-time deliveries of working copies of genes, to compensate for their mutations. The initial gene therapies helped people with a form of inherited retinal blindness to see and children with profound immune deficiencies to survive. Today, several single-gene blood, brain, muscle, and metabolic disorders are responding to one-time infusions of a gene therapy.

The biology behind a single-gene condition suggests how a particular gene therapy would be delivered, targeted, and the effect maintained. Compared to slash-and-burn technologies like standard chemo and radiation that impact cells beyond the targeted ones, a gene therapy is both rational and tailored.

For the retinal blindness, genes are injected into the nurturing cell lining beneath the rods and cones that directly provide the electrical signals to the brain that convey a visual image. Because these lining cells don’t typically divide, the delivered genes stay in place, supporting the rods and cones and maintaining vision that would otherwise vanish.

Some other gene therapies take an opposite approach, delivered into stem cells so that they can expand as the cells divide.

For skin, the challenge of gene therapy is quite different, because the cells are typically replaced so frequently – it is the very nature of the organ to constantly renew. And so application of a gene therapy is the opposite of one-and-done; it must be much more frequent.

Topical and Redosable Gene Therapy

On May 19, FDA approved Vyjuvek, a gene therapy for DEB. The announcement from Krystal Biotech terms it “the first-ever redosable gene therapy.”

Mutation in the collagen gene COL7A1 lies behind DEB, one of two major components of connective tissue. In healthy skin, collagen proteins assemble into fibrils that knit the epidermis to the dermis below, a little like mozzarella cheese anchoring the layers of a lasagna. Without COL7A1 collagen, the skin layers detach, and painful and debilitating blisters and wounds arise. Daily.

Affected kids with a recessive form – RDEB – are sometimes called “butterfly children” because their skin is so delicate, like the insect’s fragile wings. But the image conjured bears no resemblance to the reality of extremities rendered useless with the constant blistering, peeling, bleeding, and scarring.

The slightest touch instantly raises painful blisters as the skin peels away. Removing bandages is agony, but must be done daily, for a lifetime. The condition can lead to vision loss, disfigurement, and other complications, some fatal.

RDEB is inherited from two carrier parents. A dominant form – DDEB – is less severe, blistering the hands, feet, knees, and elbows.

DEB has been a candidate for a gene therapy since 2002. This DNA Science post from 2018 traces the history of the efforts.

Patients as their Own Controls

The just-approved gene therapy delivers working copies of the COL7A1 collagen gene aboard herpes simplex viruses, tweaked to only replicate in affected skin cells. A health care provider places droplets of Vyjuvek gel on a patient’s wounds once a week.  

Two clinical trials were conducted and results published in December. One, in The New England Journal of Medicine, evaluated 30 people, aged 1 to 44, who have RDEB and one with DDEB. Two similarly-sized wounds were located on each participant, and one treated weekly with the gene therapy and the other with placebo. At 24 weeks, the wounds were compared. Of the Vyjuvek-treated wounds 65% had completely closed compared to only 26% of placebo-treated wounds. Earlier results were published in Nature Medicine.

Primary investigator M. Peter Marinkovich, MD, director of the Blistering Disease Clinic at Stanford Health Care, calls DEB a devastating disease. “Until now, doctors and nurses had no way to stop blisters and wounds from developing on dystrophic EB patient skin and all we could do was to give them bandages and helplessly watch as new blisters formed. Vyjuvek topical gene therapy changes all of this. (It) both heals patient wounds and prevents skin from re-blistering because it actually corrects the underlying skin defect of dystrophic EB. Because it’s safe and easy to apply directly to wounds, it doesn’t require a lot of supporting technology or specialized expertise, making Vyjuvek highly accessible even to patients who live far away from specialized centers.”