Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease

Edmund C. Lee, Tania Valencia, Charles Allerson, Annelie Schairer, Andrea Flaten, Matanel Yheskel, Kara Kersjes, Jian Li, Sole Gatto, Mandeep Takhar, Steven Lockton, Adam Pavlicek, Michael Kim, Tiffany Chu, Randy Soriano, Scott Davis, John R. Androsavich, Salma Sarwary, Tate Owen, Julia KaplanKai Liu, Graham Jang, Steven Neben, Philip Bentley, Timothy Wright, Vishal Patel

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD.

Original languageEnglish (US)
Article number4148
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lee, E. C., Valencia, T., Allerson, C., Schairer, A., Flaten, A., Yheskel, M., Kersjes, K., Li, J., Gatto, S., Takhar, M., Lockton, S., Pavlicek, A., Kim, M., Chu, T., Soriano, R., Davis, S., Androsavich, J. R., Sarwary, S., Owen, T., ... Patel, V. (2019). Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease. Nature communications, 10(1), [4148]. https://doi.org/10.1038/s41467-019-11918-y