Inhibition of Huntingtin Synthesis by Antisense Oligodeoxynucleotides

Nellemann, Christine; Abell, Kathrine; Nørremølle, Anne; Løkkegaard, Thomas; Naver, Bjarke; Røpke, Carsten; Rygaard, Jørgen; Sørensen, Sven Asger; Hasholt, Lis

doi:10.1006/mcne.2000.0872

Cited by 35 publications

(30 citation statements)

References 42 publications

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“…This observation demonstrated that lowering mHtt levels would likely be beneficial for the treatment of HD. Several groups, including ours, have now shown that it is possible to reduce the levels of mHtt mRNA post-transcriptionaly using a variety of strategies that include antisense oligonucleotides, DNA enzymes, ribozymes and siRNAs in culture cells (Boado et al, 2000;Chen et al, 2005;Hasholt et al, 2003;Nellemann et al, 2000;Omi et al, 2005;Park et al, 2004;Yen et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo

Denovan‐Wright

Rodríguez-Lebrón

Lewin

et al. 2008

Neurobiology of Disease

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Gene transfer strategies to reduce levels of mutant huntingtin (mHtt) mRNA and protein by targeting human Htt have shown therapeutic promise in vivo. Previously, we have reported that a specific, adeno-associated viral vector (rAAV)-delivered short-hairpin RNA (siHUNT-2) targeting human Htt mRNA unexpectedly decreased levels of striatal-specific transcripts in both wild-type and R6/1 transgenic HD mice. The goal of this study was to determine whether the siHUNT-2-mediated effect was due to adverse effects of RNA interference (RNAi) expression in the brain. To this end, we designed two catalytically active hammerhead ribozymes directed against the same region of human Htt mRNA targeted by siHUNT-2 and delivered them to wild-type and R6/1 transgenic HD mice. After 10 weeks of continuous expression, these ribozymes, like siHUNT-2, negatively impacted the expression of a subset of genes in the striatum. This effect was independent of rAAV transduction and specific to the targeting of a unique sequence in human Htt mRNA. After consideration of the known potential RNAi-specific toxic mechanisms, only cleavage of an unintended RNA target can account for the data reported herein. Thus, long-term rAAV-mediated RNAi in the brain does not, in and of itself, negatively affect striatal gene expression. These findings have important implications in the development of therapeutic RNAi for the treatment of neurological disease.

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Section: Introductionmentioning

confidence: 99%

Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo

Denovan‐Wright

Rodríguez-Lebrón

Lewin

et al. 2008

Neurobiology of Disease

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“…Early cell culture screens of HTT exon 1 silencing performed with a small number of ASOs found the greatest activity with oligos targeting the initiation codon [35,36]. Later systematic screens across full-length mouse and human HTT identified oligos with high activity and species selectivity [25], and species-specific HTT silencing has been demonstrated by ICV infusion of human HTT-specific MOE ASO to the YAC128 transgenic mouse model of HD.…”

Section: Reviewmentioning

confidence: 99%

Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases

Southwell

Skotte

Bennett

et al. 2012

Trends in Molecular Medicine

115

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“…Successful delivery of ASO into NT2 cells leads to the down regulation of mutant huntingtin and reduction of aggregate formation (Nellemann et al, 2000). The ASO and RNAi perform their knock down function by nonallele-selective and allele selective manner for an e.g.…”

Section: Targeting Mutant Huntingtin Rna: Antisense Oligonucleotide (mentioning

confidence: 99%