Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells PMID: 18925943

ADC Targets in Oncology

2026-04-10

Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells

J Transl Med. 2008 Oct 16;6:59. doi: 10.1186/1479-5876-6-59.

Elizabeth A DiBlasio-Smith ¹ , Maya Arai , Elaine M Quinet , Mark J Evans , Tad Kornaga , Michael D Basso , Liang Chen , Irene Feingold , Anita R Halpern , Qiang-Yuan Liu , Ponnal Nambi , Dawn Savio , Shuguang Wang , William M Mounts , Jennifer A Isler , Anna M Slager , Michael E Burczynski , Andrew J Dorner , Edward R LaVallie

Affiliations

Abstract

Background: LXRs (Liver X Receptor alpha and beta) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse Cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds.

Objective: Blood markers of LXR Agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators.

Methods: Transcript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative Reverse Transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRalpha, LXRbeta, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated ex vivo with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623.

Results: A single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR Agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRalpha and LXRbeta, and all cell types significantly increased ABCA1 and ABCG1 expression upon ex vivo LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription.

Conclusion: Peripheral blood cells express LXRalpha and LXRbeta, and respond to LXR Agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.