Herpes vs devastating skin disease

Have you ever plucked loose skin near your nail, ripping off a tiny strip of good skin too?

Albeit very small, that wound can be painful. Now imagine that it is not just a little strip that peels off, but an entire sheet. And it does not detach only when pulled, but at the slightest touch. Even a hug opens wounds, even a caress brings you pain. This is life with recessive dystrophic epidermolysis bullosa (RDEB), the most severe form of dystrophic pidermolysis bullosa (DEB).

Herpes becomes a therapy

DEB is a rare genetic disease of the skin that affects 3 to 10 individuals per million people

(prevalence is hard to nail down for rare diseases). A cure is still far off, but there is good

news for patients. Last May, the US FDA (Food and Drug Administration) approved Vyjuvek (beremagen geperparvec) to treat skin wounds in DEB. Clinical studies showed that it speeds up healing and reduces pain.

Vyjuvek is the first gene therapy for DEB. It is manufactured by Krystal Biotech and - get this- it is a tweaked version of the herpes virus. Yes, you got that right, the virus causing blisters and scabs has become the primary ally against a devastating skin disease.

This approval is a milestone for gene therapies, as Vyjuvek is the first gene therapy

- based on the herpes virus,

- to apply on the skin as a gel,

- approved for repeated use.

This article describes how DEB, and especially RDEB, affects the skin and wreaks havoc on

the body; the following article will explain how Vyjuvek works.

DEB disrupts skin integrity

We carry around six to nine pounds of skin. Yet we often forget its importance: it stops

germs and UVs, softens blows, regulates body temperature and makes us sensitive to

touch. Diseases that compromise the skin are therefore devastating.

These essential functions rely on the organisation of the skin in three layers: epidermis,

dermis and hypodermis (Figure 1).

Typically, a Velcro strap of the protein collagen VII firmly anchors the epidermis to the

dermis. The gene COL7A1 contains the instructions on how to produce collagen VII. In DEB, mutations in COL7A1 result in the production of a faulty collagen VII. As the Velcro strap is weakened, the epidermis becomes loosely attached to the dermis.

Mutations in one copy of COL7A1 cause the dominant form of the disease (DDEB),

mutations in both copies cause RDEB. With one copy of the gene still functional, the skin still produces some collagen VII, when both copies are mutated, little to no collagen VII is left. Therefore, RDEB is more severe than DDEB. In people with RDEB, the skin can slide off at the slightest touch and even gentle rubs can cause blisters and tears (Figure 2).

Living with RDEB

Life with RDEB is gruelling and life expectancy doesn't exceed 30 years old.

Wounds are very painful, slow to heal and get infected easily. The risk of developing an

aggressive skin cancer is higher. The constant scarring can cause limb deformities. In

addition, blisters can appear in the mouth, oesophagus, eyes and other organs.

There is no cure for DEB for now; treatments can only improve the quality of life. Careful

dressing of wounds promotes healing and prevents infections. Painkillers are used to ease

pain. Special diets are required. And, to no one's surprise, physical activities must be

avoided.

Treating RDEB

Over the past decade, cell and genetic engineering advances have sparked the search for a cure. Scientists have explored two main alternatives to restore the production of collagen VII in the skin.

The first approach is based on transferring skin cells able to produce collagen VII.

Despite promising results, this approach treats only tinyl patches of skin, requires treatments in highly specialised centres and it may cause cancer.

The second approach is the one Vyjuvek followed. Scientists place the genetic information to make collagen VII in a modified virus and apply it to a wound. There, the virus infects skin cells, providing them with a new COL7A1 gene to use. These cells now produce a functional collagen VII and can patch the damage up.

We already know which approach came up on top. Vyjuvek speeds up the healing of

wounds as big as a smartphone. Professionals can apply it in hospitals, clinics or even at the patient’s home. And it uses a technology that does not cause cancer.

But how does Vyjuvek work? And why did scientists choose the herpes virus to build

Vyjuvek? We will find the answer in the following article. And since perfection does not

belong to biology, we will also discuss the limitations of this remarkable gene therapy.

NOTES:

1. DEB is part of a group of four inherited conditions, collectively named epidermolysis

bullosa (EB), where the skin loses integrity. EB is also known as “Butterfly syndrome”

because the skin becomes as fragile as a butterfly’s wing. These conditions are EB

simplex, junction EB, dystrophic EB and Kindler EB.

2. Most gene therapies are based on modified, or recombinant in science jargon,

adenoassociated viruses, which I reviewed for Scientia News.

3. Over 700 mutations have been reported. They disrupt collagen VII and its function

with various degrees of severity. Consequently, RDEB and DDEB display several

clinical phenotypes.

4. Two studies have adopted this approach: in the first study, Siprashvili and colleagues

(2016) grafted ex vivo retrovirally-modified keratinocytes, the main cell type in the

epidermis, over the skin of people with RDEB; in the second study, Lwin and

colleagues (2019) injected ex vivo lentivirally-modified fibroblasts in the dermis of

people with RDEB.

Written by Matteo Cortese, PhD