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 | |
| State | Published - Dec 1 2019 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease. / Lee, Edmund C.; Valencia, Tania; Allerson, Charles; Schairer, Annelie; Flaten, Andrea; Yheskel, Matanel; Kersjes, Kara; Li, Jian; Gatto, Sole; Takhar, Mandeep; Lockton, Steven; Pavlicek, Adam; Kim, Michael; Chu, Tiffany; Soriano, Randy; Davis, Scott; Androsavich, John R.; Sarwary, Salma; Owen, Tate; Kaplan, Julia; Liu, Kai; Jang, Graham; Neben, Steven; Bentley, Philip; Wright, Timothy; Patel, Vishal.
In: Nature communications, Vol. 10, No. 1, 4148, 01.12.2019.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=85072143491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072143491&partnerID=8YFLogxK
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 -