The skin breaks at the touch, and there are wounds everywhere: in order to cure the disease, they are forced to cover their skin with viruses.

"will you dream of living a day without pain?"

"even when I sleep, I can feel the pain. The pain seems to be somewhere in my mind, and I always knew it was there. "

For ordinary people, the skin is naturally soft and tough. Feet can walk on the ground, hands can touch all kinds of objects, even if subjected to some friction, the skin is not easily broken.

So it's hard to realize that the structure of the skin is so robust because some important proteins work between the epidermis and the dermis, holding them together. Only those who lack these proteins will realize their value.

Type VII collagen is one of those proteins. Without this substance, the epidermis is difficult to anchor on the dermis, and the slightest friction can cause blisters on the skin. Because of this, some children are born with "fragile" skin, even if they engage in soft physical activities, the skin of many parts of the hands, feet, knees and so on are easy to crack, so it is full of wounds, and some are difficult to heal over the years.

The disease is called dystrophic epidermolysis bullosa (dystrophic epidermolysis bullosa,DEB). The skin is as fragile as butterfly wings, so it is also known as "butterfly disease". Patients may live in pain every day and have never even experienced what it feels like to be painless.

The pain is caused by a mutation in a gene that prevents type VII collagen from being synthesized properly, making the skin structure unstable. Among them, recessive mutations are often more dangerous than dominant mutations. In severe cases, scars in the mouth and esophagus can cause difficulties in chewing and swallowing, making people malnourished. In addition, the skin between fingers (or toes) may fuse, joints may be deformed, vision may be lost, and skin cancer may occur. Many patients die in early adulthood because of a variety of complications.

Recently, scientists at Stanford University have found a way to control skin cracking in the case of recessive dystrophic dermatolysis bullosa (RDEB), an ointment that allows the skin to produce its own type VII collagen, which can help heal the wound and keep it from cracking for months. This ointment has achieved remarkable results in phase 1 and phase 2 clinical trials. The team published their findings in the journal Nature Medicine.

Infect skin cells with virus

In our skin, there is a thin basement membrane at the junction of the epidermis and dermis. Normally, anchoring fibrils (anchoring fibrils) are responsible for connecting the dermal extracellular matrix to the epidermal basement membrane, which is essential for the strength and stability of the skin structure. The main component of anchor fibril is type VII collagen (C7).

If the C7 protein cannot be synthesized normally, the anchor fiber will be difficult to work, the connection between the dermis and the epidermis can not be guaranteed, the skin layer and layer will be easily separated, and blisters will be formed from the dermis. Dystrophic dermatolysis bullosa (DEB) is one such disease.

The gene that encodes C7 protein is called COL7A1. When it mutates, the ability of skin cells to synthesize C7 protein may be affected, or it may not be produced at all, or the amount of protein produced may be insufficient, or the protein produced may be abnormal, all of which can make the skin vulnerable and make people suffer from DEB: the disease caused by dominant mutation is called DDEB, and the disease caused by recessive mutation is called RDEB. Most of the patients' DEB is inherited from their parents, but the possibility of pathogenic mutation is not ruled out.

Genetic defects can cause lifelong pain, and the Stanford team hopes to use gene therapy to help ease the pain, especially in RDEB patients (from recessive disease-causing mutations). If you want defective skin to regain the ability to produce C7 protein, the most direct way is to transfer normal genes.

At this point, the virus came in handy. Insert a useful gene into the viral DNA and let it infect skin cells, and the cells will be able to use that gene. Before that, however, the choice of vector virus is very important.

The scientists used herpes simplex virus type 1 (HSV-1). The COL7A1 gene that encodes C7 protein is very large, with about 9000 base pairs. The vector virus must contain this gene, and HSV-1 can do the job. In addition, after HSV-1 enters the nucleus, it will not insert its own DNA into the host chromosome, and the host genome will not have dangerous mutations as a result of being inserted.

In addition, about 67% of humans around the world carry the virus, but in the vast majority of cases, HSV-1 can quietly lurk in the human body without causing any symptoms. This means that HSV-1 can effectively avoid the immune response, not be cleared by the body, and have a better chance to complete the mission given to it by scientists.

In the second step, scientists applied this method to mice. The mice used in the experiment were also Col7a1_flNeo recessive homozygotes, and mice of this genotype produced only 10% of the C7 protein of normal mice. The team injected intradermally at four points on the back of the mice to allow the HSV-1 virus carrying the target gene to enter the skin of the mice.

As a result, a linear distribution of C7 protein was detected at the epidermis-dermal junction on the third day after injection, while on the seventh day, scientists had found a wide continuous linear distribution of the protein on large tracts of skin. In other words, the expression of C7 protein increased significantly after the mice were injected with the virus.

The third step is to conduct clinical trials of this gene therapy.

Let the wound close completely.

Scientists conducted phase I and phase II clinical trials. The first phase mainly evaluated the safety of gene therapy and the productivity of C7 protein, and the second phase mainly evaluated the effect of gene therapy on wound healing. The team recruited a total of nine patients, three of whom were children (over 6 years old). All of them were diagnosed with systemic RDEB.

The participants received a different treatment than the mice, replacing the intradermal injection with gel on the wound, but still contained the HSV-1 virus, which carries the COL7A1 gene, to help patients produce C7 protein. The wound was smeared every 1 to 3 days for 25 days, while another wound was smeared with a virus-free placebo gel as a control.

No safety problems were reported in these patients, and increased collagen expression was in line with the team's expectations. As for wound healing, all but one wound in the experimental group was completely closed within three months after treatment, while the only exception was a chronic wound with a history of five years. It was only partially closed within one month after treatment, but it was completely closed after a second 25-day course of treatment and lasted for eight months.

In contrast, placebo gel can sometimes produce a certain repair effect, but it is not as obvious as viral gel and does not last long.

Scientists say the treatment does not permanently cure RDEB. After all, the skin cells of the human body are constantly updated, the old cells will be eliminated, and the new cells can no longer produce C7 protein. Therefore, after a course of treatment, you may have to apply it again in half a year. However, being able to control the patient's condition has encouraged the research team.

In 2017, though, there was a 7-year-old boy with epidermolysis bullosa (EB) who improved significantly after receiving a stem cell transplant. However, such invasive treatment is more complex, costly, and does not guarantee success. Michele de Luca, the biologist who led the stem cell research that year, thought it might be possible to combine the two approaches, using stem cells to treat large areas of problems and gel to treat small wounds.

"We are not like butterflies. We are much stronger than we loo