May 23, 2014

Oligonucleotide-based strategies to combat polyglutamine diseases

Nucleic Acids Research
Agnieszka Fiszer, Wlodzimierz J Krzyzosiak

Abstract

Considerable advances have been recently made in understanding the molecular aspects of pathogenesis and in developing therapeutic approaches for polyglutamine (polyQ) diseases. Studies on pathogenic mechanisms have extended our knowledge of mutant protein toxicity, confirmed the toxicity of mutant transcript and identified other toxic RNA and protein entities. One very promising therapeutic strategy is targeting the causative gene expression with oligonucleotide (ON) based tools. This straightforward approach aimed at halting the early steps in the cascade of pathogenic events has been widely tested for Huntington's disease and spinocerebellar ataxia type 3. In this review, we gather information on the use of antisense oligonucleotides and RNA interference triggers for the experimental treatment of polyQ diseases in cellular and animal models. We present studies testing non-allele-selective and allele-selective gene silencing strategies. The latter include targeting SNP variants associated with mutations or targeting the pathologically expanded CAG repeat directly. We compare gene silencing effectors of various types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing...Continue Reading

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Citations

Mentioned in this Paper

Pathogenic Aspects
Pathogenesis
Huntington's Disease Pathway
Polyglutamine
Pathogenic Organism
Cosuppression
Cell Culture Techniques
Gene Expression
Trinucleotide Repeat Expansion
Oligonucleotides

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