Large Scale Synthesis of 2′-Amino-LNA Thymine and 5-Methylcytosine Nucleosides

Madsen, Andreas Stahl; Jørgensen, Anna Søndergaard; Jensen, Troels Bundgaard; Wengel, Jesper

doi:10.1021/jo302036h

Cited by 18 publications

(21 citation statements)

References 50 publications

(97 reference statements)

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“…The 12-, 13- and 14-mer CAG ONs were synthesized in both phosphodiester (PO) and phosphorothioate (PS) backbone format. The 14-mer CAG PS ON was synthesized either as an ON including 2΄- O -methyl RNA /LNA, namely: CAG-14PS-OMe or as a CAG-14PS-gly ON where 5-methylcytosine-2΄-glycylamino-LNA substitutes the regular cytidines (see Supplementary Methods for Synthesis Details (47)). A number of mismatched and scrambled ONs were used as controls (sequences found in Table 1).…”

Section: Methodsmentioning

confidence: 99%

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Zaghloul

Gissberg

Moreno

et al. 2017

Nucleic Acids Research

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Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.

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Section: Methodsmentioning

confidence: 99%

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

Zaghloul

Gissberg

Moreno

et al. 2017

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…SNPs are of a special importance for detection of viral and cancer-related nucleic acids. Synthetic oligonucleotides containing locked nucleic acids (LNAs) are useful tools in overcoming these obstacles (Koshkin et al 1998;Hari et al 2002;Levin et al 2006;Madsen et al 2012). LNAs are synthetic nucleic acid analogues with improved biophysical properties compared to natural nucleotides.…”

Section: Terminally Labeled Oligonucleotide Probesmentioning

confidence: 99%