Year of Award

2019

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Pharmaceutical Sciences

Other Degree Name/Area of Focus

Pharmaceutial Sciences and Drug Design

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Philippe J. Diaz

Commitee Members

Erica L. Woodahl, Keith K. Parker, Kasper B. Hansen, Travis J. Wheeler

Keywords

CYP26, DX314, Keratinization Disorders, RAMBA, Retinoic Acid

Abstract

Our skin, particularly the barrier provided by the epidermis, functions as our primary protection from the harsh environment. It protects us from dangerous pathogens, allergens, ultraviolet radiation, and mechanical injury, as well as playing a major role in fluid and thermal regulation. Disruption of skin functions can lead to life-threatening consequences due to increased risk of infection, trans-epidermal water loss, and allergen sensitization. Many common skin disorders often result in a disrupted skin barrier placing patients at risk of complications.

Retinoic acid (RA) is a major component of the vitamin A pathway, which critically controls multiple skin functions including cell proliferation and differentiation, barrier maintenance and immune regulation. Retinoid-based therapies have successfully been used to treat various skin disorders, such as ichthyosis and Darier’s disease, however, the prevalence of adverse effects, including dry skin, irritation, redness, photosensitivity, and barrier dysregulation, can result in complications and poor compliance. Novel, selective, retinoic acid metabolism blocking agents (RAMBAs), intended to minimize adverse effects and improve patient outcomes, have been designed and synthesized by our lab.

In these studies, we first investigated whether our novel RAMBA, DX314, can potentiate the effects of RA, via inhibition of the RA-metabolizing enzyme, CYP26B1, in healthy human epidermis models. By studying the gene expression effects of RA, DX314, and two previous-generation RAMBAs (liarozole and talarozole), we show that DX314 does potentiate the effects of RA. Additionally, by studying its effect on epidermal histology and transepithelial electrical resistance, we discovered that DX314 displays a unique skin barrier-reinforcing property. In our second series of studies, we investigated DX314’s therapeutic potential in Darier’s disease and ichthyosis. These results confirm DX314’s ability to potentiate RA, and its barrier-reinforcing properties, in diseased skin models and suggest that DX314 has potential as a novel therapeutic agent for keratinization disorders.

Together, the studies within this dissertation show our next-generation RAMBA, DX314, is a strong candidate for further drug development in the context of keratinization disorders. If successful, DX314 could fulfill the therapeutic need for an efficacious, selective RAMBA, providing improved patient outcomes and quality of life, with greatly reduced adverse effects relative to current treatment options.

Download

Share

COinS
 

© Copyright 2019 Joachim Gwenn-Stephan Veit