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

被引：114

作者：

Lee, Edmund C. ^{[1
]}

Valencia, Tania ^{[1
]}

Allerson, Charles ^{[1
]}

Schairer, Annelie ^{[1
]}

Flaten, Andrea ^{[2
,3
]}

Yheskel, Matanel ^{[2
,3
]}

Kersjes, Kara ^{[1
]}

Li, Jian ^{[1
]}

Gatto, Sole ^{[1
]}

Takhar, Mandeep ^{[1
]}

Lockton, Steven ^{[1
]}

Pavlicek, Adam ^{[1
]}

Kim, Michael ^{[1
]}

Chu, Tiffany ^{[1
]}

Soriano, Randy ^{[1
]}

Davis, Scott ^{[1
]}

Androsavich, John R. ^{[1
]}

Sarwary, Salma ^{[1
]}

Owen, Tate ^{[1
]}

Kaplan, Julia ^{[1
]}

Liu, Kai ^{[1
]}

Jang, Graham ^{[1
]}

Neben, Steven ^{[1
]}

Bentley, Philip ^{[1
]}

Wright, Timothy ^{[1
]}

Patel, Vishal ^{[2
,3
]}

机构：

[1] Regulus Therapeut Inc, San Diego, CA 92121 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Div Nephrol, Dallas, TX 75390 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

PHOSPHOROTHIOATE OLIGONUCLEOTIDE; CYST GROWTH; MICRORNAS; FAMILY; MODEL; TOLVAPTAN; GENOMICS; DELIVERY; CLUSTER; IMPACT;

D O I：

10.1038/s41467-019-11918-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 43 条

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