Institution
Regulus Therapeutics
Company•San Diego, California, United States•
About: Regulus Therapeutics is a company organization based out in San Diego, California, United States. It is known for research contribution in the topics: microRNA & Gene silencing. The organization has 122 authors who have published 117 publications receiving 17110 citations.
Topics: microRNA, Gene silencing, Cancer, Oligonucleotide, Hepatitis C virus
Papers
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TL;DR: A methodology is described that allows the determination of the physical association of miRNA inhibitors and their targets in the context of the Argonaute complex in vivo, providing unprecedented insight into the physiological interactions of anti-miRs and the miRNA machinery.
Abstract: Aberrant expression of microRNAs (miRNAs) has been causatively linked to multiple disease pathologies while pharmacological inhibition of overexpressed miRNAs by modified oligonucleotides, termed anti-miRs, has been shown to ameliorate the disease phenotype. Anti-miRs are also widely used in academia to define miRNA-mediated regulation of gene networks in vitro and in vivo. Here, we describe a methodology that allows the determination of the physical association of miRNA inhibitors and their targets in the context of the Argonaute complex in vivo, providing unprecedented insight into the physiological interactions of anti-miRs and the miRNA machinery.
1 citations
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TL;DR: To facilitate the design of potent oligonucleotides, a sensitive high-throughput methodology is developed to compare anti-miR compounds for their ability to associate with the miRNA/Argonaute complex.
Abstract: A major challenge in the development of oligonucleotide-based microRNA (miRNA) inhibitors for therapeutic applications is the identification of candidate designs with strong affinity for the target miRNA in the context of the Argonaute complex. To this effect, distinct chemical modifications are employed along the length of the oligonucleotide aimed at strengthening the interactions with the target miRNA. However, the modification chemistry and placement can inadvertently affect the intrinsic ability of the oligonucleotide to pair with its target in the context of Argonaute. To facilitate the design of potent oligonucleotides, we developed a sensitive high-throughput methodology to compare anti-miR compounds for their ability to associate with the miRNA/Argonaute complex.
1 citations
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TL;DR: It is shown that a single-nucleotide mutation in HCV allows viral RNA amplification when miR-122 abundances are low, concomitant with changes in its tropism.
Abstract: Hepatitis C virus (HCV) depends on liver-specific microRNA miR-122 for efficient viral RNA amplification in liver cells. This microRNA interacts with two different conserved sites at the very 5’ end of the viral RNA, enhancing miR-122 stability and promoting replication of the viral RNA. Treatment of HCV patients with oligonucleotides that sequester mir-122 resulted in profound loss of viral RNA in phase II clinical trials. However, some patients accumulated in their sera a viral RNA genome that contained a single cytidine to uridine mutation at the third nucleotide from the 5’ genomic end. It is shown here that this C3U variant indeed displayed higher rates of replication than that of wild-type HCV when miR-122 abundance is low in liver cells. However, when miR-122 abundance is high, binding of miR-122 to site 1, most proximal to the 5’ end in the C3U variant RNA, is impaired without disrupting the binding of miR-122 to site 2. As a result, C3U RNA displays a much lower rate of replication than wild-type mRNA when miR-122 abundance is high in the liver. These findings suggest that sequestration of miR-122 leads to a resistance-associated mutation that has only been observed in treated patients so far, and raises the question about the function of the C3U variant in the peripheral blood.
1 citations
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TL;DR: It is shown that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels, which together regulate plasma HDL cholesterol.
Abstract: RationaleThe bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the...
1 citations
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TL;DR: This work describes a method that uses changes in Argonaute 2-RNA immunoprecipitation in response to competition by anti-miR, titrated ex vivo, as physical evidence for target validation.
Abstract: Identification and validation of microRNA (miRNA) target genes is essential for gaining a better understanding of the many different functions miRNAs have in healthy and diseased cells. From a practical standpoint, validated target genes are also useful for monitoring pharmacological activity of developmental therapeutics that modulate miRNAs, such as anti-miRNA oligonucleotides (anti-miR). Here, we describe a method that uses changes in Argonaute 2-RNA immunoprecipitation in response to competition by anti-miR, titrated ex vivo, as physical evidence for target validation.
Authors
Showing all 122 results
Name | H-index | Papers | Citations |
---|---|---|---|
David Baltimore | 203 | 876 | 162955 |
David P. Bartel | 116 | 230 | 173368 |
Peter S. Linsley | 107 | 318 | 70881 |
Balkrishen Bhat | 43 | 115 | 7957 |
Lars Karlsson | 35 | 66 | 5058 |
Adam Pavlicek | 32 | 57 | 5574 |
Aimee L. Jackson | 31 | 68 | 13213 |
Matthias John | 29 | 79 | 8136 |
Daniel J. Hogan | 29 | 92 | 3434 |
Eric G. Marcusson | 27 | 73 | 5733 |
Charles R. Allerson | 22 | 30 | 2940 |
Christine Esau | 21 | 39 | 5000 |
Steven Lockton | 20 | 48 | 1830 |
Aaron N. Chang | 20 | 29 | 3180 |
B. Nelson Chau | 16 | 24 | 2950 |