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; Vishal Patel

doi:10.1038/s41467-019-11918-y

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

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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 language	English (US)
Article number	4148
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11918-y
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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10.1038/s41467-019-11918-y

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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

Lee, EC, 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, JR, Sarwary, S, Owen, T, Kaplan, J, Liu, K, Jang, G, Neben, S, Bentley, P, Wright, T & Patel, V 2019, 'Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease', Nature communications, vol. 10, no. 1, 4148. https://doi.org/10.1038/s41467-019-11918-y

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

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.",

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

note = "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{\textquoteright}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: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-11918-y",

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

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