Inflammatory bowel diseases
T helper cells are comprised of several closely related T cell populations that play an important role in every immune response. Our work focuses on T helper cell lineage, Th17 that in characterized by production of a key cytokine, IL17 and is highly involved in chronic inflammation. The differentiation, survival and function of this population is dependent on a RORγt, a member of retinoid-related orphan receptor (ROR) family. Therefore, RORγt is an attractive target for Th17-mediated autoimmune diseases.
The difficulty in targeting RORγt relies in its high similarity to another ROR member, RORγ. RORγ and RORγt transcripts are identical except for the initial 150 bases of the 5’ region. Beside this difference the residual sequences, including DNA- and ligand-binding domains are identical. The expression of RORγt is restricted to the cells of the immune system while RORγ shows highest expression in the liver and kidney. Additionally, these factors regulate expression of different target genes. RORγt drives Th17 lineage commitment and function while RORγ regulates blood sugar and triglyceride metabolism in the liver.
We designed and selected effective RORγt-specific LNATM-Gapmer antisense oligonucleotides. Our targeting approach is highly RORγt specific and advantageous to small molecule inhibitors that target ligand binding domains of both RORγ and RORγt. In vitro data in primary human Th17 cells as well as in vivo data in different mouse IBD models show efficacy of antisense oligonucleotides after unassisted delivery. Our data provide first evidence for targeting of RORgt without safety issues of co-targeting of other ROR family members.
Secarna Pharmaceuticals GmbH