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Article
| Open Access
Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy
The GAT4A transcription factor mediates cardiac development. Here the authors identify that the 5′ UTR of GATA4 mRNA contains a double stranded structure downstream of an upstream open reading frame (uORF) that promotes uORF-mediated suppression of the main ORF.
- Omar M. Hedaya
- , Kadiam C. Venkata Subbaiah
- & Peng Yao
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Article
| Open Access
Fluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats
Delivery of anti-inflammatory microRNA (miRNA) could be beneficial for inflammatory diseases such as rheumatoid arthritis (RA). Here the authors show that a fluorinated polyamidoamine dendrimer nanoparticle delivers miR-23b to affected RA joints and reduces inflammation, joint damage and synovial cell influx.
- Haobo Han
- , Jiakai Xing
- & Quanshun Li
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Article
| Open Access
XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection
RNA viruses have been responsible for large-scale epidemics and pandemics throughout the last few centuries. Here, the authors show the design, synthesis and screening of artificial RNA endonuclease XNAzymes capable of cleaving genomic SARS-CoV-2 RNA and self-assembling into enzymatic nanostructures inhibiting cellular viral replication.
- Pehuén Pereyra Gerber
- , Maria J. Donde
- & Alexander I. Taylor
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Article
| Open Access
An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
Oligonucleotides targeting mRNA are promising therapeutic agents but suffer from poor bioavailability. Here, the authors develop reduced-charge oligonucleotides with artificial LNA-amide linkages with improved cell uptake and minimal structural deviation to the DNA:RNA duplex.
- Ysobel R. Baker
- , Cameron Thorpe
- & Tom Brown
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Article
| Open Access
Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy
The W1282X nonsense mutation in the CFTR gene causes cystic fibrosis by reducing its mRNA and functional protein levels. Here the authors developed antisense-oligonucleotide cocktails that restore CFTR protein function by gene-specific stabilization of CFTR mRNA.
- Young Jin Kim
- , Tomoki Nomakuchi
- & Adrian R. Krainer
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Article
| Open Access
DNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo
Using gene silencing to regulate lymphocyte function is a promising therapeutic approach for autommunity, inflammation and cancer. Here the authors use a heteroduplex oligonucleotide for improved potency, efficacy and longer retention times.
- Masaki Ohyagi
- , Tetsuya Nagata
- & Takanori Yokota
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Article
| Open Access
Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease caused by toxic RNA containing expanded CGG repeats. Here, the authors show that synthetic oligonucleotides targeting the RNA repeats decrease the pleiotropic effect of this toxic molecule in cellular and animal models of the disease.
- Magdalena Derbis
- , Emre Kul
- & Krzysztof Sobczak
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Article
| Open Access
Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models
C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.
- Yuanjing Liu
- , Jean-Cosme Dodart
- & Robert H. Brown Jr.
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Article
| Open Access
Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression
Restoration of normal gene expression is one way to treat monogenic disorders. Here the authors target naturally occurring non-productive alternative splicing using antisense oligonucleotides to promote the production of functional proteins.
- Kian Huat Lim
- , Zhou Han
- & Isabel Aznarez
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Article
| Open Access
Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5
Alport syndrome is a progressive inherited nephritis accompanied by sensorineural loss of hearing and ocular abnormalities, for which there is currently no effective therapy. Here, the authors develop an exon-skipping therapy using an antisense-oligonucleotide and show it is effective in mouse models.
- Tomohiko Yamamura
- , Tomoko Horinouchi
- & Kandai Nozu
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Article
| Open Access
Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
- Julio Aguado
- , Agustin Sola-Carvajal
- & Fabrizio d’Adda di Fagagna
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Article
| Open Access
HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis
Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease
- Margaux Sevin
- , Lucia Kubovcakova
- & Aurélie de Thonel
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Article
| Open Access
Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice
X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.
- Hichem Tasfaout
- , Suzie Buono
- & Jocelyn Laporte
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Article
| Open Access
Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice
Inhibition of microRNAs using antimiRs is a potential therapeutic option for a number of diseases, but systemic inhibition may cause adverse effects. Here the authors develop light-activated antimiRs directed against miR-92a, and show localized inhibition in the skin and improved wound healing in diabetic mice.
- Tina Lucas
- , Florian Schäfer
- & Stefanie Dimmeler
Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry