Differential Effects on Allele Selective Silencing of Mutant Huntingtin by Two Stereoisomers of 伪,尾-Constrained Nucleic Acid

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• 作者：Michael E. 脴stergaard ; B茅atrice Gerland ; Jean-Marc Escudier ; Eric E. Swayze ; Punit P. Seth
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：September 19, 2014
• 年：2014
• 卷：9
• 期：9
• 页码：1975-1979
• 全文大小：303K
• ISSN：1554-8937

文摘

We describe the effects of introducing two epimers of neutral backbone 伪,尾-constrained nucleic acid (CNA) on the activity and allele selectivity profile of RNase H active antisense oligonucleotides (ASOs) targeting a single nucleotide polymorphism (SNP) for the treatment of Huntington鈥檚 disease (HD). ASOs modified with both isomers of 伪,尾-CNA in the gap region showed good activity versus the mutant allele, but one isomer showed improved selectivity versus the wild-type allele. Analysis of the human RNase H cleavage patterns of 伪,尾-CNA modified ASOs versus matched and mismatched RNA revealed that both isomers support RNase H cleavage on the RNA strand across from the site of incorporation in the ASO鈥攁n unusual observation for a neutral linkage oligonucleotide modification. Interestingly, ASOs modified with (R)- and (S)-5鈥?hydroxyethyl DNA (RHE and SHE respectively) formed by partial hydrolysis of the dioxaphosphorinane ring system in 伪,尾-CNA also showed good activity versus the mutant allele but an improved selectivity profile was observed for the RHE modified ASO. Our observations further support the profiling of neutral and 5鈥?modified nucleic acid analogs as tools for gene silencing applications.