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 Kaplan, Kai Liu, Graham Jang, Steven Neben, Philip Bentley, Timothy Wright and Vishal Patel ()
Additional contact information
Edmund C. Lee: Regulus Therapeutics Inc.
Tania Valencia: Regulus Therapeutics Inc.
Charles Allerson: Regulus Therapeutics Inc.
Annelie Schairer: Regulus Therapeutics Inc.
Andrea Flaten: University of Texas Southwestern Medical Center
Matanel Yheskel: University of Texas Southwestern Medical Center
Kara Kersjes: Regulus Therapeutics Inc.
Jian Li: Regulus Therapeutics Inc.
Sole Gatto: Regulus Therapeutics Inc.
Mandeep Takhar: Regulus Therapeutics Inc.
Steven Lockton: Regulus Therapeutics Inc.
Adam Pavlicek: Regulus Therapeutics Inc.
Michael Kim: Regulus Therapeutics Inc.
Tiffany Chu: Regulus Therapeutics Inc.
Randy Soriano: Regulus Therapeutics Inc.
Scott Davis: Regulus Therapeutics Inc.
John R. Androsavich: Regulus Therapeutics Inc.
Salma Sarwary: Regulus Therapeutics Inc.
Tate Owen: Regulus Therapeutics Inc.
Julia Kaplan: Regulus Therapeutics Inc.
Kai Liu: Regulus Therapeutics Inc.
Graham Jang: Regulus Therapeutics Inc.
Steven Neben: Regulus Therapeutics Inc.
Philip Bentley: Regulus Therapeutics Inc.
Timothy Wright: Regulus Therapeutics Inc.
Vishal Patel: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11918-y

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