TY - JOUR
T1 - Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
AU - Lee, Edmund C.
AU - Valencia, Tania
AU - Allerson, Charles
AU - Schairer, Annelie
AU - Flaten, Andrea
AU - Yheskel, Matanel
AU - Kersjes, Kara
AU - Li, Jian
AU - Gatto, Sole
AU - Takhar, Mandeep
AU - Lockton, Steven
AU - Pavlicek, Adam
AU - Kim, Michael
AU - Chu, Tiffany
AU - Soriano, Randy
AU - Davis, Scott
AU - Androsavich, John R.
AU - Sarwary, Salma
AU - Owen, Tate
AU - Kaplan, Julia
AU - Liu, Kai
AU - Jang, Graham
AU - Neben, Steven
AU - Bentley, Philip
AU - Wright, Timothy
AU - Patel, Vishal
N1 - Funding Information:
We thank Regulus Therapeutics employees and members of the Patel Lab for their support of this project. We thank Vincente Torres and Peter Harris for guidance at the initial stage of this work. We thank Darren Wallace and the PKD biomarkers and Biomaterials Core of the University of Kansas Medical Center for providing the human primary ADPKD cyst cells. We thank Stefan Somolo for providing Pkd2F/F mice. We thank the University of Texas Southwestern O’Brien Kidney Research Core center for providing critical reagents and services. We thank InVicro, a Konica Minolta Company for providing services for MRI-imaging. The Patel lab is supported by grants from the National Institute of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673). This work is funded by Regulus Therapeutics.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11918-y
DO - 10.1038/s41467-019-11918-y
M3 - Article
C2 - 31515477
AN - SCOPUS:85072143491
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4148
ER -