STRIKE Platform Enables Kidney-Selective Gene Silencing via Megalin-Mediated Uptake

Background: Proximal tubular epithelial cells (PTECs) in the kidney are critical to solute reabsorption and systemic homeostasis and represent an attractive site for therapeutic intervention in both renal and systemic diseases. However, oligonucleotide-based therapeutics such as siRNAs have shown limited effectiveness in this compartment due to inefficient delivery. Judo Bio’s STRIKE (Selectively Targeting RNA Into KidnEy) platform enables receptor-mediated uptake of ligand-conjugated siRNAs into specific renal cell types. We leverage megalin, a highly expressed, rapidly internalized and recycled receptor on PTECs, to achieve targeted, durable gene silencing in kidney. Methods: Megalin-binding ligand-siRNA conjugates (STRIKERs) were designed and tested across various in-vitro and animal systems for enhanced delivery and activity. Drug exposure and tissue distribution were assessed using fluorescence, mass spectrometry and stem-loop qPCR. siRNA activity was quantified via qPCR, RNA sequencing, and in-situ hybridization. Animals (rodents or NHPs) were dosed subcutaneously and followed for different durations. Multiple dosing paradigms were explored, including repeat, split, and dual-target co-dosing. Safety and tolerability were evaluated across species. Results: In mice, a single dose of megalin-STRIKERs achieved dose-dependent and kidney-specific gene knockdown (>70%) with durable effects. Exposure data confirmed selective accumulation in the kidney and in PTECs. Repeat and split dosing demonstrated additive knockdown and dual-targeting siRNA co-administration resulted in simultaneous, non-interfering knockdown of multiple targets. In NHPs, the first-generation STRIKER showed effective translation with kidney specific enrichment and target gene knockdown. No adverse effects were observed in either species. Conclusion: The STRIKE platform enables potent and selective siRNA delivery to PTECs via megalin-mediated uptake. These results demonstrate successful translation across species and establish a new foundation for precision RNA-based therapies in renal and systemic diseases. STRIKE represents a promising platform for specifically targeting various solute carrier proteins for therapeutic benefit. Funding: Commercial Support - Judo Bio