DEBRA International First proof-of-principle gene therapy for disabling inherited skin disorder

First proof-of-principle gene therapy for disabling inherited skin disorder

DebRA Research

[researchmen.htm]

An Italian research team has, for the first time, demonstrated that it is possible to correct the genetic defect, and effectively ‘cure’ the treated areas of skin, in an inherited skin disorder which causes extreme disability and pain in sufferers.

Epidermolysis bullosa, or EB, is a devastating and often fatal disorder in which the outer layer of skin, the epidermis, fails to stick properly to the underlying layer of skin, and blisters or peels off at the slightest knock or rub. Epidermolysis bullosa literally means ‘blistering breakdown of skin’, and this happens because the skin lacks one type of protein that normally helps to hold the two layers together. The protein is defective because the gene which encodes it is also faulty.

The Italian team, led by Professor Michele de Luca at the University of Modena, has reported this week in the international journal Nature Medicine* that, by introducing a corrected copy of the gene into patches of badly affected skin of an EB patient, it has been possible to cure these patches of skin: one year after treatment, the patches remain free of blisters, infections, and any inflammation or immune response. This work is the first proof-of-principle that a gene therapy might provide a solution to this otherwise incurable disease, and will give some hope to the hundreds of thousands of sufferers worldwide.

The gene therapy approach developed by De Luca and his team involved removing small patches of skin from the palm of the hand of the patient, a 36-year-old man with a type of EB known as JEB, or junctional EB. In JEB, the protein which is defective is called laminin. Epidermal skin stem cells from the patches of skin were grown in the laboratory, and correct copies of the laminin gene were inserted into the skin stem cells. [Epidermal stem cells are the cells in skin that are able to keep dividing to produce new epidermal cells and constantly renew our skin.] The corrected skin cells containing the laminin gene were then grown into sheets of skin in the laboratory, until they were of a size suitable for forming skin grafts.

The patient had badly affected areas of skin on the upper front part of his legs where the skin was extremely fragile, with non-healing wounds: these were the areas selected for grafting with corrected skin. The team removed the outer epidermal layer of the patient’s skin in these areas, and then grafted corrected skin onto four patches on one leg, and five patches on the other. Each patch was about 55 square centimetres, and a total skin area of 500 square centimetres was grafted.

The patient’s skin in these grafted areas had completely healed after one week and, a year later, these corrected areas of skin look normal and remain strong: they do not blister or itch even after being rubbed hard, although surrounding areas of uncorrected skin still blister even without any friction applied. Small samples of skin taken from grafted skin several months, and at a year, after transplant were examined under the microscope. This showed that the skin looked normal, and that the outer epidermis was firmly attached to the underlying dermis layer of the skin. With these initial promising results, De Luca’ team plans to continue with a systematic, stepwise replacement of other areas of this patient’s skin over the next 2 to 3 years.

This study shows for the first time that genetically corrected epidermal stem cells can be used to generate a functioning, self-renewing epidermis in patients, and the successful outcome of this clinical trial paves the way for gene therapy of other types of EB, as well as for some other genetic skin diseases.