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Genetic Linkage

Gene Therapy for the "Butterfly Children"

Videos of the "butterfly children” are difficult to watch. The name comes from the delicate skin of people who have epidermolysis bullosa, which is reminiscent of the fragility of a butterfly’s wings. The slightest touch evokes painful blisters and peeling skin.

“I was born with the worst disease you never heard of,” says Rafi Lily in one video. “I know mom doesn’t want to hurt me, but taking off bandages is hard. It feels like fire is beating me up and sharp dogs teeth are digging into me. But we’ll have to do it all over tomorrow and the next day and every day for the rest of my life.”

In another video, Mikey has red marks on his face and neck, with gauze wrapped around his arms and legs. “He has blisters all over. Every time you go to remove a bandage, you’re touching an open sore,” says his mom Heather as the little boy screams in the background.

“The worst disease you never heard of” is recessive dystrophic epidermolysis bullosa – RDEB. It’s inherited from carrier parents.

“At a birth, nurses and doctors know right away and call for a pediatric dermatology consult,” says John Maslowski, president and chief executive officer of Fibrocell, which is conducting a phase 1/2 clinical trial for a gene therapy for RDEB. But the disease is so rare that sometimes it isn’t obvious. According to an article in the Washington Post, doctors repeatedly asked one mother if she had a herpes infection when they saw the missing skin on the bottoms of her newborn’s feet. When skin fell away when a nurse attempted to diaper the baby, RDEB seemed the more likely diagnosis.

Care Centers But No Long-Term Treatments

Children born with EB are referred quickly to an EB Center. In the US they’re at Stanford University, Columbia University, Cincinnati Children’s, the Mayo Clinic and Colorado Children’s Hospital. The UK has four centres of excellence. Parents quickly learn that they’ll be providing the intensive care, which consists of daily full body bandage changes and use of antibiotics and antiseptics.

“These aren’t like ace bandages, they’re made of special polymers that have low adhesion so they don’t tear the skin if a parent pulls a bandage off. Many families have problems with reimbursement for supplies, which can run to $10,000 a month in bandages alone,” says Maslowski. That’s much more of a problem in the US, where insurers may balk. The National Health Service in the UK has a Wound Care Distribution Program that supplies bandages to patients.

The daily bandage changes, pricking of blisters, and removing flaky skin aren’t all. Bathing takes hours. Complications include anemia, malnutrition from mouth and esophagus sores that make eating nearly impossible, squamous cell carcinoma, and frequent hospitalizations for surgical procedures to cut fingers free from “mitten hands” and open the esophagus to ease eating. Over time rigid joints and deformities emerge as the damaged skin shrinks and tightens muscles and tendons into contractures.

If ever a disease was in need of a more lasting treatment, RDEB may be it.

Ex Vivo Gene Therapy Supplies Type VII Collagen

In healthy skin, anchoring fibrils made mostly of type VII collagen protein knit the thin epidermis to the dermis below. In RDEB, any of 200 mutations prevents fibril formation. The epidermis peels away, leaving sores, erosions, scars, and wounds. RDEB affects 1100 to 2500 people in the US, with about 2 in every million births.

Gene therapy uses viruses to deliver functional COL7A1 genes, which encode the collagen, into cells taken from patients and growing outside the body (“ex vivo”), and then injects the doctored self-cells into selected areas of skin. Several variations on the theme are underway – at King’s College in the UK, Holostem Terapie Avanzate s.r.i. in Austria, and Necker Hospital for Sick Children and Genegraft in France, and in the US. The trials vary in the type of viral vectors that deliver the genes and whether the target is keratinocytes (from the epidermis) or fibroblasts (from the dermis).

Rather than a “one and done” introduction of gene-corrected cells into the bloodstream and meant to circulate everywhere, RDEB gene therapy is localized, and would ideally coincide with patients’ routine hospitalizations, treating one skin area at a time. But it isn’t like a game of whac-a-mole, targeting spots at random. “In younger children with RDEB, wounds start emerging on the body before they become immobile with contractures by their early teens. One of our clinical strategies is to treat earlier and prevent these small areas from becoming larger areas,” explains Maslowski. And instead of covering as much anatomical terrain as possible, focusing on certain areas may better improve quality of life – like the waistline, the mouth, and the fingers, he adds.

The Idea Evolves

I love to follow clues in the citations of a well-researched paper to trace the evolution of a treatment, from animal models and human cells, to human cells growing in or on animal models, through clinical trials. The long trajectory is why I hate the expression “find a cure,” as if a magical elixir is lurking in a corner of a lab, waiting for a lucky researcher to stumble upon it.

It isn’t surprising that the first publication describing gene therapy for RDEB is from 2002. That was when the field was beginning to emerge from the clinical trial stranglehold that followed two deaths and leukemia in gene therapy trials, described in my book The Forever Fix: Gene Therapy and the Boy Who Saved It. Researchers at the University of Southern California corrected patients’ keratinocytes and fibroblasts and grew sheets of human skin, which they then grafted onto immune-deficient mice. There, the saran-wrap-like patches built the anchoring fibrils missing in the patients’ skin. In 2003, the
same group found that fibroblasts alone did the trick.

In 2008 the group from the UK injected unaltered fibroblasts from healthy donors into 5 people with RDEB, who then made anchoring fibrils. A mix of collagen VII from the fibroblasts plus scarce or abnormal protein from the patients apparently helped. But cell therapy without genetic correction doesn’t last very long.

In 2016, the French researchers grafted gene-corrected human skin fibroblasts onto mice. The cells, from RDEB patients, had received functioning COL7A1genes via a retroviral vector. The grafts produced the collagen and voilà, fibrils formed and adhered epidermis to dermis. Alain Hovnanian and his co-workers plan to treat three patients with their own (autologous) corrected cells in the second half of 2018.

Meanwhile, the Stanford researchers, working with Abeona Therapeutics, had begun grafting sheets of autologous genetically corrected keratinocytes onto wounds in patients in 2010, culminating in a report in 2016 on four patients. So far, the “gene-corrected autologous cell therapy,” called EB-101, is safe and effective: fibrils form, wounds heal, and no signs of cancer or immune rejection have appeared. The improvements diminished with time, suggesting the need for booster treatments – but that’s ok. The work received Regenerative Medicine Advanced Therapy Designation from the FDA on January 29, and phase 3 clinical trial planning is underway.

Fibrocell is targeting autologous fibroblasts, and released interim findings in September 2017 on the effect of their product, FCX-007, on five wounds treated in three adults. At the 12 week mark four of the wounds were more than 70% healed and collagen VII produced, although anchoring fibrils weren’t yet observed. But the cells are making the right stuff in the right place, safely. Coming up: phase 2, for children. Partner Intrexon provides the genetics expertise to Fibrocell’s dermatology expertise.

Fibrocell has an interesting background, reminiscent of the Seinfeld episode when Jerry makes fun of dermatologists for treating giant zits, then is reminded of skin cancer. In 2011 FDA approved Laviv azficel-T, a “personalized aesthetic cell therapy” that delivers patients’ own fibroblasts, mass-produced in a dish, to plump up smile lines with collagen made in situ. Company goals expanded into burn and acne scars, and then in 2012, as gene therapy’s success neared, turned to rare inherited skin diseases with unmet needs. RDEB clearly fit the bill.

With several companies deploying gene-boosted cells against RDEB, future patients may have truly healing options – not just the daily bandaging. Summed up Maslowski, “The hope is that over time we can get a lasting effect in an area on the body and then, when the patient comes back for other surgeries, treat different areas. We can freeze the cells, so we don’t have to regrow them. The technology will create a coverage program for patients over time, to cover most of their skin.”

Images of skin supplied by DEBRA UK (www.debra.org.uk), the UK’s national charity supporting those directly affected by, and working with, Epidermolysis Bullosa (EB).


Dystrophic Epidermolysis Bullosa Research Association of America (DEBRA)


Epidermolysis Bullosa Research Foundation

Epidermolysis Bullosa Medical Research Foundation

This post first appeared at my DNA Science blog at Public Library of Science.

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