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Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control epidermis: changes after oral
Elizabeth Pavez Loriè1, Agneta Gånemo, Marcel Borgers
1Department of Medical Sciences/Dermatology, Uppsala University, Uppsala, Sweden.
Abstract:
Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.
Insights
Liarozole treatment for lamellar ichthyosis altered retinoid-regulated gene expression in the epidermis. This suggests liarozole offers therapeutic benefits by modulating these genes, particularly in Ichthyin mutation patients.
Area of Science:
- Dermatology
- Genetics
- Pharmacology
Background:
- Lamellar ichthyosis is a genetic keratinization disorder.
- Liarozole is a novel treatment targeting cytochrome P450 (CYP26)-mediated catabolism of all-trans retinoic acid.
Purpose of the Study:
- To investigate the expression of retinoid-related genes in ichthyotic epidermis.
- To evaluate changes in gene expression before and after liarozole treatment.
Main Methods:
- Compared mRNA expression of CRABPII, KRT2, KRT4, CYP26A1, CYP26B1, IL-1α, and TNF-α in biopsies from patients and controls.
- Analyzed gene expression changes in 11 genetically defined lamellar ichthyosis patients before and after 4 weeks of liarozole treatment (75 or 150 mg/day).
- Correlated gene expression with therapeutic response in patients with TGM1 and Ichthyin mutations.
Main Results:
- Elevated cellular retinoic acid binding protein II (CRABPII) expression was observed in untreated patients compared to controls.
- Liarozole treatment led to decreased KRT2 and TNF-α mRNA expression, with trends toward increased KRT4 and CYP26A1.
- Therapeutic response was better in Ichthyin mutation patients than TGM1 mutation patients; no dose-dependent response was noted.
Conclusions:
- Liarozole demonstrates therapeutic effects in lamellar ichthyosis.
- The mechanism involves mild modulation of retinoid-regulated genes in the epidermis.
- Gene expression changes suggest increased retinoid stimulation, supporting liarozole's efficacy.
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