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. 2009 Sep:1175:24-31.
doi: 10.1111/j.1749-6632.2009.04975.x.

Allele-selective inhibition of mutant huntingtin by peptide nucleic acid-peptide conjugates, locked nucleic acid, and small interfering RNA

Jiaxin Hu  1 , Masayuki Matsui, David R Corey
Affiliations

Allele-selective inhibition of mutant huntingtin by peptide nucleic acid-peptide conjugates, locked nucleic acid, and small interfering RNA

Jiaxin Hu et al. Ann N Y Acad Sci. 2009 Sep.

Abstract

The ability to inhibit expression of a mutant allele while retaining expression of a wild-type protein might provide a useful approach to treating Huntington's Disease (HD) and other inherited pathologies. The mutant form of huntingtin (HTT), the protein responsible for HD, is encoded by an mRNA containing an expanded CAG repeat. We demonstrate that peptide nucleic acid conjugates and locked nucleic acids complementary to the CAG repeat selectively block expression of mutant HTT. The selectivity of inhibition is at least as good as that shown by a small interfering RNA targeted to a deletion polymorphism. Our data suggest that antisense oligomers are promising subjects for further development as an anti-HD therapeutic strategy.

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Figures

Figure 1
Figure 1
Chemical Structures of PNA and LNA.
Figure 2
Figure 2
(a) Graph of selectivity versus difference repeat number (number of mutant repeats minus number of wild-type repeats) for REP19. (b) Graph of IC50 value versus repeat number for REP19. (c) Graph of IC50 value versus repeat number for REP19N.
Figure 3
Figure 3
Comparison of allele-specific silencing strategies: siRNAs that target polymorphisms versus PNAs and an LNA that target a CAG repeat. (a) Inhibition of HTT expression by two different siRNAs that target a deletion polymorphism. (b–e) Inhibition of HTT expression by siRNA S4, LNA/REP, PNA REP19, and REP19N respectively.
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