This is an on-going international project with partners at the University of Huddersfield, at the Freie Universität Berlin (Germany), the Medical University Innsbruck (Austria) and industrial partners.
We have generated 3D skin models which mimic the skin of our ichthyosis patients (gene mutation, lack of protein, epidermal barrier defect, changes in gene expression profile, trans-epidermal water loss, thickening of skin, scaly skin). We use these models to study any new drug, thus minimising the use of animals in our research. Please see below our paper Eckl et al from 2011 for further reading on how full-thickness skin models are generated. The link to the paper can be found here: http://www.jidonline.org/article/S0022-202X(15)35399-9/fulltext
In 2015 we showed that thermo-responsive poly(N-isopropylacrylamide)-polyglycerol-based nanogels are excellent transporters for cutaneous applications due to the native thermal gradient of human skin. The skin is cold on the surface and warm inside the body. Once the thermo-responsive nanogel has travelled into the skin (while passing the very thick horny layer) it releases its cargo (this is the protein, Tgase-1, missing in the patient skin).
“The proof of concept was provided by transglutaminase 1-loaded nanogels which efficiently delivered the protein into transglutaminase 1-deficient skin models resulting in a restoration of skin barrier function. In conclusion, thermoresponsive nanogels are promising topical delivery systems for biomacromolecules” (from the Witting et al. 2015 abstract, which can be found in full here: https://www.ncbi.nlm.nih.gov/pubmed/25791808)
To meet legislative demands, we will now analyse side effects of our new drug in extended in-vitro (cell culture, skin model) and in-vivo (animal) cytotoxicity analysis. We are further required to establish the highest to tolerate dose and reduce any risk for future users. This is a drug for an orphan disease and we seek to receive EMA orphan drug status soon.
Relevant references for this section:
- Alnasif, N., Zoschke, C., Fleige, E., Brodwolf, R., Boreham, A., Ruhl, E., Eckl, K.M., Merk, H.F., Hennies, H.C., Alexiev, U., et al. (2014). Penetration of normal, damaged and diseased skin – An in vitro study on dendritic core-multishell nanotransporters. JControl Release 185, 45-50.
- Eckl, K.M., Weindl, G., Ackermann, K., Kuchler, S., Casper, R., Radowski, M.R., Haag, R., Hennies, H.C., and Schafer-Korting, M. (2014). Increased cutaneous absorption reflects impaired barrier function of reconstructed skin models mimicking keratinisation disorders. Exp Dermatol 23, 286-288.
- Witting, M., Molina, M., Obst, K., Plank, R., Eckl, K.M., Hennies, H.C., Calderon, M., Friess, W., and Hedtrich, S. (2015). Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules. Nanomedicine, 10.
- Eckl, K.M., Alef, T., Torres, S., and Hennies, H.C. (2011). Full-Thickness Human Skin Models for Congenital Ichthyosis and Related Keratinization Disorders. J Invest Dermatol 131, 1938-1942.
- Aufenvenne, K., Larcher, F., Hausser, I., Duarte, B., Oji, V., Nikolenko, H., Del, R.M., Dathe, M., and Traupe, H. (2013). Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. AmJHumGenet 93, 620-630.
- Aufenvenne, K., Rice, R.H., Hausser, I., Oji, V., Hennies, H.C., Rio, M.D., Traupe, H., and Larcher, F. (2012). Long-term faithful recapitulation of transglutaminase 1-deficient lamellar ichthyosis in a skin-humanized mouse model, and insights from proteomic studies. JInvest Dermatol 132, 1918-1921.
- Eckl, K.M. (2014). Update: advanced methods in three-dimensional organotypic tissue engineering for congenital ichthyosis and other rare keratinization disorders. Br J Dermatol 171, 1289-1290.