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Allele-Selective In...
Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG Repeat
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Gagnon, Keith T. (author)
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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, Jyoti (author)
- Uppsala universitet,Bioorganisk kemi
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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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(creator_code:org_t)
- 2010-11-08
- 2010
- English.
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 49:47, s. 10166-10178
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- Biochemistry
- Biokemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
-
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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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Biochemistry
- By the university
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Uppsala University