Judo Bio, a biotechnology company focused on developing oligonucleotide medicines for kidney delivery, has announced the presentation of preclinical data demonstrating a mechanism for the uptake and trafficking of ligand-siRNA conjugates via megalin receptors. This mechanism enables targeted gene knockdown in proximal tubule epithelial cells (PTECs) of the kidney. The data is being showcased at Kidney Week 2024, the annual meeting of the American Society of Nephrology, held in San Diego, CA, from October 24-27.
These findings highlight the capabilities of Judo Bio’s STRIKE (Selectively Targeting RNA Into KidnEy) platform, which aims to discover ligand-siRNA conjugates that utilize the natural process of receptor-mediated endocytosis for delivering oligonucleotide therapeutics to specific kidney cell populations. Megalin-STRIKERs, the company’s ligand-siRNA conjugates, bind to megalin on PTECs, facilitating drug uptake and gene silencing of targeted mRNA. In its initial drug development programs, Judo Bio is focusing on megalin-STRIKERs to silence mRNA expression of specific solute carrier (SLC) proteins, which may inhibit the uptake of circulating metabolites associated with systemic diseases.
Dr. Ora A. Weisz, an author of the poster presentation and Professor of Medicine, Cell Biology, and Clinical and Translational Science in the Division of Renal-Electrolyte at the University of Pittsburgh, noted, “Our understanding of endocytic trafficking in kidney proximal tubule cells has advanced rapidly in recent years. This approach to harness the endocytic pathway for selective RNA delivery to specific kidney cells provides a valuable opportunity to target and silence solute carrier proteins to address various systemic diseases.”
The preclinical data presented at Kidney Week examined megalin ligand-conjugated siRNA (megalin-STRIKERs) in a differentiated opossum kidney PTEC cell line, which mimics proximal tubule morphology and functions similarly to animal kidneys. Key findings from the study include:
- Ligand-siRNAs were taken up by opossum kidney cells in a time- and concentration-dependent manner, primarily from the apical surface.
- The uptake of ligand-siRNA conjugates was megalin-dependent and was effective with various megalin ligands.
- Megalin ligand-siRNA conjugates resulted in significant gene knockdown across multiple targets, with effects lasting up to 40 days in mice.
The poster presentation from Judo Bio at Kidney Week can be accessed on the company’s website.
Dr. Alfica Sehgal, Chief Scientific Officer of Judo Bio, expressed enthusiasm about the findings, stating, “We are excited to share data that illustrate how megalin’s endogenous receptor-mediated endocytosis can facilitate gene silencing in PTECs. Understanding the mechanisms behind gene silencing informs our optimization of the first megalin-STRIKERs targeting SLC proteins. Modulating the function of specific SLCs is a recognized strategy for treating various systemic diseases, and employing an RNAi approach opens up significant therapeutic possibilities due to its specificity.
