Laquinimod targets the aryl hydrocarbon receptor (AhR) pathway in periphery and brains of naïve and EAE mice (P2.365)

Objective: To elucidate laquinimod’s broad molecular effects in a tissue-specific manner using a genome-wide approach.

Background: Laquinimod is a once-daily oral treatment currently in clinical trials for relapsing-remitting and primary-progressive multiple sclerosis (MS), and Huntington disease (HD). While laquinimod’s mechanism-of-action (MoA) is not fully elucidated, effects on the peripheral innate immune system as well as on resident cells within the CNS have been observed. It was recently shown that deletion of AhR in the peripheral immune system abrogates the effect of laquinimod in EAE.

Design/Methods: Naive or MOG-EAE female C57BL/6 mice were treated with vehicle or 25 mg/kg laquinimod for 13 days, after-which RNAseq was performed on blood, splenocytes, and brain from six mice per arm.

Results: Laquinimod differentially modulated AhR-related genes in EAE and naïve mice in all tissues. In EAE mice, the highest fold-change induction among the 11,713 (blood), 2484 (splenocytes), and 1505 (brain) genes significantly modulated by laquinimod (FDR<0.05, |FC|>1.5) was demonstrated in either Cyp1a1 or Ahrr, both prototypical AhR-regulated genes. Cyp1a1 and Ahrr were also induced by laquinimod in all three tissues in naïve mice, and together with another AhR-effector, Cyp1b1, constituted the only genes significantly modulated by laquinimod in naïve mice brain. In addition to the AhR pathway, laquinimod modulated multiple disease-related genes within the NF-κB pathway in all three tissues in EAE mice. Pro-inflammatory monocyte (M1) genes were reduced specifically in brain subsequent to laquinimod administration, consistent with previous reports demonstrating a laquinimod-induced reduction in M1 cell infiltration to the CNS.

Conclusions: Laquinimod induces the AhR pathway in both periphery and CNS while affecting immune cells in a tissue-specific manner. Given the reported critical role of AhR in laquinimod efficacy in animal models, further studies are underway to deepen our understanding of these mechanisms and their relevance to therapeutic effects in MS and HD.

Study Supported by:

Teva Pharmaceutical Industries Netanya Israel

Disclosure: Dr. Birnberg has received personal compensation for activities with Teva Pharmaceutical Industries as an employee. Dr. Kaye has received personal compensation for activities with Teva Pharmaceutical Industries Ltd. as an employee. Dr. Kaye holds stock and/or stock options in Teva Pharmaceutical Industries Ltd. Dr. Kaye has received research support from Teva Pharmaceuticals. Dr. Fowler has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Weiner has received personal compensation for activities with Immuneering Corporation as an employee. Dr. Cabellero has received personal compensation for activities with Immuneering Corporation as an employee. Dr. Barash has received personal compensation for activities with Immuneering Corporation. Dr. Raymond has received personal compensation for activities with Teva Pharmaceutical Industries as an employee. Dr. Ben-Eliezer has received research support from Teva Pharmaceutical Industries. Dr. Fishbein has received personal compensation for activities with Teva Pharmaceutical Industries as an employee. Dr. Orbach has received personal compensation for activities with Teva Pharmaceutical Industries as an employee. Dr. Laifenfeld has received personal compensation for activities with Teva Pharmaceutical Industries. Dr. Laifenfeld holds stock and/or stock options in Teva Pharmaceutical Industries. Dr. Laufer has received personal compensation for activities with Teva Pharmaceutical Industries Ltd as an employee. Dr. Grossman has received personal compensation for activities with Teva Neuroscience as an employee.