Aptamer-based suppression of anti-GBM immunogenicity

Overview

This research program develops nucleic acid aptamers designed to bind the Goodpasture Syndrome antigen, the non-collagenous domain 1 (NC1) of the α3 chain of type IV collagen (α3(IV)NC1), and block autoantibody interaction with this target. Anti-GBM (glomerular basement membrane) disease is an autoimmune condition in which the immune system attacks the kidneys and lungs, and current therapies rely on broad immunosuppression. By providing a targeted molecular shield against the specific antigen, this approach aims to suppress disease-driving autoantibody activity while minimizing broader immune suppression.

The platform builds on demonstrated expertise in aptamer-based heavy metal toxicity protection in C. elegans models and cell-based assay development. Aptamers offer advantages over traditional biologics, including synthetic production, chemical stability, and the ability to be modified for nuclease resistance. The technology has been validated in proof-of-concept studies showing that aptamers can fully restore normal brood size and behavior in toxin-exposed organisms, demonstrating functional rescue through specific molecular binding.

Technical specifications

Aptamer platform capabilities:

• Selection of DNA aptamers with high specificity for the α3(IV)NC1 antigen through contractor-led selection processes
• ELISA-based confirmation of aptamer binding and competitive inhibition of antibody–antigen association
• Development of nuclease-resistant variants including locked nucleic acid (LNA), morpholino, and mirror DNA configurations to enhance in vivo stability
• Cell-based assay expertise for validating aptamer function and specificity

Validation approach:

• Purification of α3(IV)NC1 antigen for use in binding assays
• Comparative testing of antisense and scrambled aptamer controls to confirm sequence-specific activity
• Quantitative ELISA assessment of antibody blocking efficacy
• Pathway to in vivo testing in mouse models following aptamer optimization

Technology readiness level

The program is at an early-to-mid stage of development. The underlying aptamer technology has been validated in C. elegans models for heavy metal toxicity, demonstrating functional rescue through specific molecular binding. The α3(IV)NC1-targeted aptamer work is in the discovery and validation phase, with high-confidence aptamer candidates and nuclease-resistant variants anticipated within 12 months. At the conclusion of the proposed study, optimized aptamers will be ready for testing in mouse models, representing a key step toward preclinical development for anti-GBM disease and potentially other autoimmune conditions involving well-characterized antigens.