Potent and systematic RNAi mediated silencing with single oligonucleotide compounds

Lapierre, Jennifer; Salomon, William E.; Cardia, James; Bulock, Karen; Lam, Jessica; Stanney, William; Ford, Glenna; Smith-Anzures, Bernice; Woolf, Tod M.; Kamens, Joanne; Khvorova, Anastasia; Samarsky, Dmitry

doi:10.1261/rna.2399411

Cited by 7 publications

(8 citation statements)

References 13 publications

(12 reference statements)

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“…AMOs are synthetic oligonucleotides with reverse complementary sequences to mature miRNAs that can tightly bind to their miRNA targets with high specificity as well as optimal stability and pharmacokinetics necessary to block miRNA function. Since naked RNA is rapidly degraded in the blood stream secondary to significant nuclease enzymatic degradation [Czauderna et al 2003], AMOs are chemically modified to confer nuclease stability, increase binding affinity, as well as facilitate entrance into the cell and miRNA-induced silencing complex [Lapierre et al 2011]. These oligonucleotide chemical modifications may include nucleotide modifications to the phosphate backbone and/or sugar or use of nonribose backbones [Lennox and Behlke, 2011].…”

Section: Mirnas As Therapy In Ibd: Design and Delivery Of Mirna Agentsmentioning

confidence: 99%

The emerging role of miRNAs in inflammatory bowel disease: a review

Chapman

Pekow

2014

Therap Adv Gastroenterol

140

106

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Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.

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Section: Mirnas As Therapy In Ibd: Design and Delivery Of Mirna Agentsmentioning

confidence: 99%

The emerging role of miRNAs in inflammatory bowel disease: a review

Chapman

Pekow

2014

Therap Adv Gastroenterol

140

106

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“…Synthetic small interfering RNAs (siRNAs) have been widely used to transiently knockdown gene expression in cultured cells for loss of function (LoF) analyses. In mammalian cell models it has been shown that allele-specific silencing of disease genes with siRNA can be achieved by targeting either a linked single-nucleotide polymorphism (SNP) or the disease mutation directly (Lapierre et al, 2011). For a polyglutamine neurodegenerative disorder, the SNP was employed to design a siRNA able to silence the mutant Machado-Joseph disease/ spinocerebellar ataxia type 3 allele while sparing expression of the WT allele (Miller et al, 2003).…”

Section: Therapeutic Targeting Of Rnamentioning

confidence: 99%

Neurodegeneration as an RNA disorder

Johnson

Noble

Tartaglia

et al. 2012

Progress in Neurobiology

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Neurodegenerative diseases constitute one of the single most important public health challenges of the coming decades, and yet we presently have only a limited understanding of the underlying genetic, cellular and molecular causes. As a result, no effective disease-modifying therapies are currently available, and no method exists to allow detection at early disease stages, and as a result diagnoses are only made decades after disease pathogenesis, by which time the majority of physical damage has already occurred. Since the sequencing of the human genome, we have come to appreciate that the transcriptional output of the human genome is extremely rich in non-protein coding RNAs (ncRNAs). This heterogeneous class of transcripts is widely expressed in the nervous system, and is likely to play many crucial roles in the development and functioning of this organ. Most exciting, evidence has recently been presented that ncRNAs play central, but hitherto unappreciated roles in neurodegenerative processes. Here, we review the diverse available evidence demonstrating involvement of ncRNAs in neurodegenerative diseases, and discuss their possible implications in the development of therapies and biomarkers for these conditions.

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“…For example, including two 2′- O -Me-RNA nucleotides at the 5′-end of the siRNA reduces its ability to enter the miRNA pathway [117,119]. siRNA designs that ensure loading of the correct guide strand into RISC can also help to reduce off-target effects [120–126]. …”

Section: Control Experiments: You Can Never Have Too Manymentioning

confidence: 99%

Silencing disease genes in the laboratory and the clinic

Watts

Corey

2011

The Journal of Pathology

391

309

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Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past twenty years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology.

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Potent and systematic RNAi mediated silencing with single oligonucleotide compounds

Cited by 7 publications

References 13 publications

The emerging role of miRNAs in inflammatory bowel disease: a review

The emerging role of miRNAs in inflammatory bowel disease: a review

Neurodegeneration as an RNA disorder

Silencing disease genes in the laboratory and the clinic

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