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Allele-Selective In...
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Gagnon, Keith T.
(author)
Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG Repeat
- Article/chapterEnglish2010
Publisher, publication year, extent ...
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2010-11-08
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American Chemical Society (ACS),2010
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-139357
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-139357URI
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https://doi.org/10.1021/bi101208kDOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Huntington's disease (HD) is a currently incurable neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene. Therapeutic approaches include selectively inhibiting the expression of the mutated HTT allele while conserving function of the normal allele. We have evaluated a series of antisense oligonucleotides (ASOs) targeted to the expanded CAG repeat within HTT mRNA for their ability to selectively inhibit expression of mutant HTT protein. Several ASOs incorporating a variety of modifications, including bridged nucleic acids and phosphorothioate internucleotide linkages, exhibited allele-selective silencing in patient-derived fibroblasts. Allele-selective ASOs did not affect the expression of other CAG repeat-containing genes and selectivity was observed in cell lines containing minimal CAG repeat lengths representative of most HD patients. Allele-selective ASOs left HTT mRNA intact and did not support ribonuclease H activity in vitro. We observed cooperative binding of multiple ASO molecules to CAG repeat-containing HTT mRNA transcripts in vitro. These results are consistent with a mechanism involving inhibition at the level of translation. ASOs targeted to the CAG repeat of HTT provide a starting point for the development of oligonucleotide-based therapeutics that can inhibit gene expression with allelic discrimination in patients with HD.
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Pendergraff, Hannah M.
(author)
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Deleavey, Glen F.
(author)
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Swayze, Eric E.
(author)
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Potier, Pierre
(author)
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Randolph, John
(author)
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Roesch, Eric B.
(author)
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Chattopadhyaya, JyotiUppsala universitet,Bioorganisk kemi
(author)
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Damha, Masad J.
(author)
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Bennett, C. Frank
(author)
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Montaillier, Christophe
(author)
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Lemaitre, Marc
(author)
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Corey, David R.
(author)
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Uppsala universitetBioorganisk kemi
(creator_code:org_t)
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In:Biochemistry: American Chemical Society (ACS)49:47, s. 10166-101780006-29601520-4995
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Gagnon, Keith T.
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Pendergraff, Han ...
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Deleavey, Glen F ...
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Swayze, Eric E.
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Potier, Pierre
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Randolph, John
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Roesch, Eric B.
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Chattopadhyaya, ...
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Damha, Masad J.
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Bennett, C. Fran ...
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Montaillier, Chr ...
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Lemaitre, Marc
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Corey, David R.
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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Biochemistry
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Uppsala University