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TALEN-mediated gene inactivation in skin cells as a therapeutic approach for EB

New scientific publication from the Koller Working Group

Researchers from the EB House have recently successfully developed the modern gene therapy method TALEN to inactivate mutant genes in skin cells. The results of this study were published in the journal "Journal of Investigative Dermatology".

TALEN are artificially engineered enzymes that can cut the gene DNA at a defined position. As a result, defective genes can be switched off, or new healthy genes can be incorporated.

In order to develop and test this method as a potential gene therapy approach, the researchers used skin cells from a patient with epidermal ichtyosis (EI). EI is a genetic skin disease caused by mutations in the keratin genes K10 and K1. Similar to EB simplex (EBS), in which the keratin genes K14 and K5 are affected, the mutations in EI also lead to defective proteins and consequently to instability of the keratin cell skeleton leading to blistering.

The aim of this study was to inactivate the mutant copy (allele) of the K10 gene in patient cells. The intact allele should then take over the full function of both alleles and produce sufficient amounts of stable K10.

For this purpose, TALEN were designed, which are able to specifically target the K10 gene, and cut the DNA at this site. This frequently leads to the degradation of the mutant K10 allele so that no more defective K10 protein can be produced. Accordingly, only the healthy K10 protein should be present in the skin cells. These specific TALENS were delivered into the patient cells in the laboratory and then tested for their stability using molecular biological methods.
It could be shown that the elimination of the mutant K10 allele leads to the stabilization of the keratin skeleton in the treated patient cells, which as a result resembled healthy skin cells. Further, no side effects have been detected.

This study laid the ground to adapt the TALEN gene therapy method to skin cells of patients with EBS and possibly other EB forms, and to bring this approach to clinics for EB patients.

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