Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
| Autor: | Michael Kim, Mandeep Takhar, S. Neben, John R. Androsavich, Tania Valencia, Vishal Patel, Philip Bentley, Kara Kersjes, Scott Davis, Edmund C. Lee, Tiffany Chu, Randy Soriano, Jian Li, Sole Gatto, Kai Liu, Salma Sarwary, Andrea Flaten, Adam Pavlicek, Steven Lockton, Matanel Yheskel, Charles R. Allerson, Wright Timothy, Julia Kaplan, Graham Jang, Tate Owen, Annelie Schairer |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Oligonucleotides General Physics and Astronomy Disease urologic and male genital diseases 0302 clinical medicine Polycystic kidney disease Medicine Cyst Gene Regulatory Networks Tissue Distribution lcsh:Science Kidney Polycystic Kidney Diseases Multidisciplinary Pharmaceutics female genital diseases and pregnancy complications 3. Good health medicine.anatomical_structure Kidney Tubules 030220 oncology & carcinogenesis miRNAs Science Autosomal dominant polycystic kidney disease General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Polysome Animals Humans RNA Messenger Gene Cell Proliferation PKD1 Base Sequence business.industry urogenital system General Chemistry medicine.disease Hematopoiesis Mice Inbred C57BL Disease Models Animal Macaca fascicularis MicroRNAs 030104 developmental biology Cancer research lcsh:Q business HeLa Cells |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-11918-y |
| Popis: | 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. Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD. |
| Databáze: | OpenAIRE |
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