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Institution

Regulus Therapeutics

CompanySan 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.


Papers
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Journal ArticleDOI
18 Dec 2008-Nature
TL;DR: It is shown that microRNA-21 regulates the ERK–MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function and confirms miR-21 as a disease target in heart failure and establishes the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.
Abstract: MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.

2,206 citations

Journal ArticleDOI
TL;DR: A new class of lipid-like delivery molecules, termed lipidoids, are described, that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-Stranded antisense 2′-O-methyl (2′-OMe) oligoribonucleotides targeting microRNA (miRNA).
Abstract: The safe and effective delivery of RNA interference (RNAi) therapeutics remains an important challenge for clinical development. The diversity of current delivery materials remains limited, in part because of their slow, multi-step syntheses. Here we describe a new class of lipid-like delivery molecules, termed lipidoids, as delivery agents for RNAi therapeutics. Chemical methods were developed to allow the rapid synthesis of a large library of over 1,200 structurally diverse lipidoids. From this library, we identified lipidoids that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-stranded antisense 2'-O-methyl (2'-OMe) oligoribonucleotides targeting microRNA (miRNA). The safety and efficacy of lipidoids were evaluated in three animal models: mice, rats and nonhuman primates. The studies reported here suggest that these materials may have broad utility for both local and systemic delivery of RNA therapeutics.

1,127 citations

Journal ArticleDOI
TL;DR: The types of off-target effects of siRNAs and methods to mitigate them are described to help enable effective application of this exciting technology.
Abstract: Small interfering RNAs (siRNAs) are widely used to study gene function owing to the ease with which they silence target genes, and there is considerable interest in their potential for therapeutic applications. In a remarkably short time since their discovery, siRNAs have entered human clinical trials in various disease areas. However, rapid acceptance of the use of siRNAs has been accompanied by recognition of several hurdles for the technology, including a lack of specificity. Off-target activity can complicate the interpretation of phenotypic effects in gene-silencing experiments and can potentially lead to unwanted toxicities. Here, we describe the types of off-target effects of siRNAs and methods to mitigate them, to help enable effective application of this exciting technology.

936 citations

Journal ArticleDOI
30 Jun 2011-Nature
TL;DR: It is shown that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice and caveolin-1, a critical regulator of the insulin receptor, is identified as a direct target gene of miR- 103/107, as a new target for the treatment of type 2 diabetes and obesity.
Abstract: Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.

881 citations


Authors

Showing all 122 results

NameH-indexPapersCitations
David Baltimore203876162955
David P. Bartel116230173368
Peter S. Linsley10731870881
Balkrishen Bhat431157957
Lars Karlsson35665058
Adam Pavlicek32575574
Aimee L. Jackson316813213
Matthias John29798136
Daniel J. Hogan29923434
Eric G. Marcusson27735733
Charles R. Allerson22302940
Christine Esau21395000
Steven Lockton20481830
Aaron N. Chang20293180
B. Nelson Chau16242950
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20212
20201
20195
20182
201712
20168