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EB researcher identified the requirements for the success of an ex vivo gene therapy in JEB

New scientific publication with EB House contribution

The upper layer of the skin (epidermis) renews itself approximately every 4 weeks. A small cell population of epidermal stem cells in the skin is responsible to generate new epidermal cells (keratinocytes) through cell division, thus they are essential for the regeneration of the skin. Stem cells also have the ability to self-renew throughout whole life of an individual. This unfortunately is not the case for patients with Junctional EB (JEB), whose skin cells have mutations in the laminin-332 gene. These patients lose their stem cells in the skin with increasing age, the origin of which was not yet clear.

Researchers from Italy, Germany and Austria, who together have performed gene therapy studies in JEB patients have now found a possible explanation for the stem cell depletion in JEB skin. The results have been published in the scientific journal Cell Reports.

The low number of stem cells in the JEB skin can hamper the success of an ex vivo gene therapy in these patients, where keratinocytes and stem cells are obtained and expanded from a small skin biopsy. These cells are subsequently gene corrected and grafted onto wounds. Only the presence of corrected stem cells in the grafted skin assures a permanent and stable wound closure.

The researchers have found that the protein called Yes-associated protein (YAP) plays an important role in sustaining epidermal stem cells in the skin. They discovered that YAP is dramatically decreased in JEB keratinocytes compared to healthy keratinocytes, and hypothesized that the lack of the laminin-332 protein in JEB cells triggers the YAP inactivation, which was confirmed through laboratory experiments. By depleting laminin-332 in healthy skin cells, the level of YAP decreased similar to those in JEB cells and lead to stem cell loss. The other way round, introduction of a healthy laminin-332 protein into JEB keratinocytes rescued the YAP activity and thus preserved the stem cells. These results suggest that a laminin-332 gene therapy can rescue the JEB stem cells and suggest that an ex vivo gene therapy should be performed as soon as possible in children with JEB before the exhaustion of stem cells in the patient’s skin.

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