Eradication of K1/K10 in the epidermis – a model for Bullous Congenital Ichthyosiform Erythroderma (BIE/EHK) therapy

Update 2012

We have finished the project and published it recently in the highly renowned international scientific journal Journal of Cell Science (L. Wallace, L. Roberts-Thompson, J. Reichelt. 2012. Deletion of K1/K10 does not impair epidermal stratification but affects desmosomal structure and nuclear integrity. Journal of Cell Science. Epub ahead of print). (Wallace et al., 2012)

The K1/K10 deficient mice which we generated during the project, revealed very interesting basic knowledge on the function of keratins in the epidermis, however, they also clearly showed that a deletion of both keratins, K1 and K10, is not compensated by another keratin pair (e.g. K5/K14) and the skin is therefore not resilient in the absence the K1/K10 pair. The research project demonstrated that deletion of the keratin pair K1/K10 is not an option for a therapy of BCIE patients as the skin is too fragile. The results of the project were presented at one national and two international conferences:

1) K1/K10 filaments are dispensable for epidermal barrier formation. J. Reichelt, Annual Meeting of the British Society for Investigative Dermatology, April 2011, Manchester. Oral presentation.

2) K1/K10 filaments are not required for epidermal differentiation. J. Reichelt, European Conference of Intermediate Filaments in Health and disease, June 2011 in Mykonos, Greece. Oral and poster presentation.

3) K1/K10 filaments are dispensable for epidermal barrier formation. J. Reichelt, Gordon Research Conference (GRC) on Epithelial Differentiation and Keratinization, July 2011, Mount Snow, VT, USA. Poster presentation.

As our research established that the deletion of K1 and K10 is no possible in patients, we are now concentrating on deleting the mutant genes only. We are working on a gene therapy for keratin-associated blistering skin diseases which involves an ex-vivo gene therapy and are currently trying to find funding for this. We recently showed that our approach of deleting a specific gene works in keratinocyte stem cells of mice (Höher, T., Wallace, L., Khan, K., Cathomen, T., Reichelt, J. (2011). Highly efficient zinc-finger nuclease-mediated disruption of an eGFP transgene in keratinocyte stem cells without impairment of stem cell properties. Stem Cell Rev. [Epub ahead of print]), and we are confident that we can also develop the approach further to apply it to patients in the future.

Progress is always slow in research but I am sure that we are going in the right direction with our gene therapy approach and we will continue to work hard to develop a therapy for blistering skin diseases.

PD Dr. Julia Reichelt
Lecturer in Epidermal Stem Cell Biology

The Project

Patients suffering from bullous congenital ichthyosiform erythroderma (BCIE) carry a mutation in either keratin 1 (K1) or keratin 10 (K10) protein. These two proteins act as partners and are, alongside other proteins, responsible for skin stability. If either K1 or K10 is defective, skin resilience is reduced. This causes blistering in infants which is later compensated by skin thickening and pronounced ichthyosis. There is no cure for the disease and retinoids used to reduce the ichthyosis in adult patients increase the blistering.
Research for this form of disorder aims to reduce the production of the defective keratin. The diversity of K1 and K10 mutations found in BCIE patients complicates a general treatment of the disease and demands patient-specific therapy addressing keratin mutations individually. One way to eradicate the need for individual therapies would be to eliminate the keratin pair K1/K10 altogether using a universal drug suitable for all patients irrespective of their specific mutation. The removed keratin pair could be replaced by another keratin pair (K5/K14) which also exists normally in skin.
The project aim is to establish whether the deletion of K1/K10 in skin can be fully substituted by the existing keratin pair K5/K14 which in turn may aid the development of a BCIE therapy to suppress the production of mutant keratins.