Topical application of proteins as a new therapy option for the treatment of severe, genetic skin diseases

• Applicant: Professorin Dr. Sarah Hedtrich
• Subject Area: Pharmacy ; Dermatology
• Term: from 2012 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213514507

The aim of our project is an efficient and targeted transport of functional proteins into the viable epidermis using innovative drug delivery systems. This approach aims to allow a local substitution of proteins that are endogenously missing or defective because of a genetic defect. The project investigates a novel therapeutic approach for the treatment of severe, genetic skin diseases such as ichthyosis vulgaris or autosomal recessive congenital ichthyosis (ARCI). As for today, the treatment of these diseases is exclusively symptomatic and the underlying cause is not addressed. In the first funding period, the applicants Hedtrich and Hennies have demonstrated successfully that a topical application of proteins is possible using microneedles, polyglycerol (PG)-based nanogels, or hyaluronic acid (HA) hydrogels. Through targeted inactivation of the genes encoding for transglutaminase 1 (TGM1), 12R-lipoxygenase (ALOX12B), and epidermal lipoxygenase-3 (ALOXE3), we have generated skin disease models for ARCI in vitro, which are characterized by a disturbed skin barrier function. Most interestingly, the skin barrier function of TGM1-deficient disease models was successfully reconstituted following the topical application of the enzyme transglutaminase 1 (TGase-1) loaded onto nanogels. These results provided the proof of concept that locally substituted proteins are functional in the viable epidermis and can compensate for the defect of disease associated genes. Hence, we have shown that PG nanogels were effective and promising protein delivery systems. Therefore, we will focus on these nanogels, which will be further developed and optimized, in the second funding period. We will solely use human reconstituted skin for these experiments since with these models interspecies related problems are avoided. Moreover, we want to demonstrate that human skin models are suitable preclinical test systems and can be used for comprehensive drug testing in vitro. To this end, we will also generate less well characterized proteins and develop methods to determine their specific activity in tissues and cultured cells. The treated 2D and 3D cell cultures will be thoroughly characterized using molecular and cell biological methods to understand the mechanisms of protein activity and the effects of nanogels on a functional and molecular level.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Co-Investigator: Privatdozent Hans-Christian Hennies, Ph.D.