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Kidney Week

Abstract: TH-PO380

Antisense Oligonucleotides Target Proximal Tubular Epithelial Cells in Kidney

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)


  • Markert, Sabrina, Philipps Universität Marburg, Marburg, Germany
  • Hofmeister, Andreas, Philipps-University Marburg, Marburg, Germany
  • Stenzel, Dana Katharina, Philipps-University Marburg, Marburg, Germany
  • Hoyer, Joachim, Marburg Philipps-University, Marburg, Germany
  • Garn, Holger, Philipps-University Marburg, Marburg, Germany
  • Grgic, Ivica, Philipps-University Marburg, Marburg, Germany

Developing, refining and deploying new drugs to target specific molecules in cell types and tissues of interest is crucial for advancing towards precision medicine. Antisense oligonucleotides (ASO) are chemically synthesized, short DNA oligomers that can be applied to target specific mRNAs via hybridization and degradation, thus resulting in a reduced synthesis of related proteins. Recent data suggest that newer, more stable and effective generations of ASO may be of therapeutic value, including in humans. However, our understanding of the biodistribution and efficacy of systemically delivered ASO in organs is insufficient.


Here, we investigated the distribution, cell incorporation and gene knockdown efficiency of ASO specifically in kidney cells in vitro and in vivo using an unbiased approach.


First, we designed and generated several eGFP-specific LNA Gapmer-type ASO and tested for eGFP knockdown potency in vitro. Promising candidates were amplified and then used in two transgenic mouse models of ubiquitous, constitutive eGFP-expression. EGFP-mice were i.p. injected with ASO directed against eGFP or control ASO for five to ten days, sacrificed and organs harvested for analyses. Comprehensive immunohistological studies in kidney using cell-specific staining techniques found distinct and robust eGFP suppression in proximal tubular epithelial cells (PTEC) but not in other renal cell types including the TAL, collecting duct, interstitium and endothelial cells. To study the biodistribution and dynamics of systemic ASO in more detail, we administered fluorophore-labeled ASO to wildtype mice and found overwhelming ASO enrichment in PTEC, suggesting highly preferential ASO incorporation in this segment of the nephron. In line, temporary exposure of mammal PTEC to labeled ASO in vitro resulted in rapid and sustained increases in intracellular fluorescence, indicating efficient ASO uptake by PTEC.


In summary, our data provide strong evidence for a differentiated biodistribution and cellular internalization of ASO in renal tissue with systemic delivery, implicating important differences in ASO-mediated knockdown efficacy and favoring, overall, PTEC as potential target cells. This disparity in ASO accessibility and hence expectable impact needs to be considered when defining therapeutic targets in kidney.


  • Government Support - Non-U.S.