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

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Pattern recognition receptors, like Mincle (Clec4e), are crucial in regulating inflammation.
• Mincle overactivation, driven by damage-associated molecular patterns in sterile inflammation, contributes to various diseases.
• Current Mincle-targeted therapies face limitations, including antibody production challenges and a lack of small-molecule inhibitors.

Purpose of the Study:

• To develop and characterize a novel, highly specific DNA aptamer targeting Mincle.
• To evaluate the therapeutic potential of this Mincle-targeting aptamer in preclinical models.

Main Methods:

• Development of a DNA aptamer (AptMincle) designed to neutralize Mincle.
• Assessment of AptMincle's binding affinity and specificity to human and mouse Mincle.
• In vitro evaluation of AptMincle's ability to inhibit Mincle activation pathways (Syk and P65 phosphorylation) induced by trehalose-6,6-dibehenate (TDB).
• In vivo testing of a modified, bio-stable aptamer (AptMincleDRBL) in a dextran sodium sulfate (DSS)-induced mouse model of ulcerative colitis.

Main Results:

• AptMincle demonstrated high-affinity, selective binding to both human and mouse Mincle.
• AptMincle effectively reduced Mincle activation in vitro, comparable to a neutralizing antibody.
• AptMincleDRBL significantly reduced disease activity in a DSS-induced ulcerative colitis model in a dose- and sequence-dependent manner.

Conclusions:

• A highly specific DNA aptamer (AptMincle) with antagonistic Mincle function was developed.
• This aptamer represents a promising alternative for investigating Mincle-associated diseases.
• Mincle-targeting aptamers hold translational potential as a novel biologic therapy for inflammatory bowel disease (IBD).