Mincle-binding DNA aptamer demonstrates therapeutic potential in a model of inflammatory bowel disease

Matthew Stephens; Keith Keane; Simon Roizes; Shan Liao; Pierre-Yves von der Weid

doi:10.1016/j.omtn.2022.05.026

Mincle-binding DNA aptamer demonstrates therapeutic potential in a model of inflammatory bowel disease

Mol Ther Nucleic Acids. 2022 Jun 2:28:935-947. doi: 10.1016/j.omtn.2022.05.026. eCollection 2022 Jun 14.

Authors

Matthew Stephens¹, Keith Keane¹, Simon Roizes¹, Shan Liao², Pierre-Yves von der Weid¹

Affiliations

¹ Inflammation Research Network, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
² Department of Microbiology, Immunology & Infectious Disease, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Abstract

Pattern recognition receptors such as Mincle (Clec4e) play a significant role in the regulation of inflammation. Enhanced signaling of Mincle through the release of damage-associated molecular patterns during sterile inflammation has been shown to be important in the progression and manifestation of several diseases. A limitation to Mincle-targeted therapeutics is the feasibility of human-scale antibody therapy and the lack of alternative small-molecule inhibitors. Herein, we describe a highly specific neutralizing DNA aptamer targeting Mincle and demonstrate its therapeutic potential. Our data demonstrate that AptMincle selectively binds to both human and mouse Mincle with high affinity and is able to directly target and reduce Mincle activation. AptMincle can specifically reduce trehalose-6,6-dibehenate (TDB)-induced Syk and P65 phosphorylation in vitro in a manner comparable to that of the commercially available neutralizing antibody in vitro. Moreover, a bio-stable modified aptamer, AptMincle^DRBL, was successful in reducing disease activity in a dextran sodium sulfate (DSS)-induced model of ulcerative colitis in a dose- and sequence-dependent manner. The results present an alternative, highly specific DNA aptamer with antagonistic function for use in the investigation of Mincle-associated diseases. The data also show the translational potential of Mincle-targeting aptamers as a new category of biologic therapy in the treatment of inflammatory bowel disease (IBD).

Keywords: MT: Oligonucleotides: Therapies and Applications; Mincle; aptamer; inflammation; inflammatory bowel disease; ulcerative colitis.