Abstract
Background: Retinoid-based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non-specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings. Objectives: Characterize the therapeutic potential of recently discovered, CYP26-selective RAMBA, DX308. Materials and Methods: Preliminary in vitro assessment of potential off-target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways. Results: In vitro, DX308 does not interact with off-target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid-responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs. Conclusions: These preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid-responsive skin ailments.
| Original language | English |
|---|---|
| Article number | e22 |
| Journal | Skin Health and Disease |
| Volume | 1 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jun 2021 |
Funding
We would like to thank Drs. B. Bienfait and J.S. Blairvacq (Clinique St Luc, Namur-Bouge, Belgium) for skin samples which provided primary KCs for this study. Special thanks to Valérie De Glas, Benoît Balau and Haoming Liu for their help and advice with various KC experiments. We would also like to thank the people at Northwestern University Skin Biology and Diseases Resource-based Center (P30AR075049) for their assistance with the studies of ichthyotic KCs. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease of the National Institute of Health: R44AR069416 (P. Diaz, D. Mendes, J. Kreitinger, L. Walker and A.S. Paller) and P20GM103546 (P. Diaz, D. Mendes and J.G.S. Veit). The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Health. We would like to thank Drs. B. Bienfait and J.S. Blairvacq (Clinique St Luc, Namur‐Bouge, Belgium) for skin samples which provided primary KCs for this study. Special thanks to Valérie De Glas, Benoît Balau and Haoming Liu for their help and advice with various KC experiments. We would also like to thank the people at Northwestern University Skin Biology and Diseases Resource‐based Center (P30AR075049) for their assistance with the studies of ichthyotic KCs. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease of the National Institute of Health: R44AR069416 (P. Diaz, D. Mendes, J. Kreitinger, L. Walker and A.S. Paller) and P20GM103546 (P. Diaz, D. Mendes and J.G.S. Veit). The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Health.
| Funders | Funder number |
|---|---|
| Clinique St. Luc Bouge | |
| R44AR069416, P20GM103546 | |
| Northwestern University | P30AR075049 |