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Caenorhabditis elegans as a Model System for Discovering Bioactive Compounds Against Polyglutamine-Mediated Neurotoxicity
Published on: September 21, 2021
Oligonucleotide-based strategies to combat polyglutamine diseases
Agnieszka Fiszer1, Wlodzimierz J Krzyzosiak2
1Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
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. We discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases.
Insights
Oligonucleotide-based therapies show promise for treating polyglutamine (polyQ) diseases by silencing mutant gene expression. This review examines antisense oligonucleotides and RNA interference strategies in preclinical models.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Polyglutamine (polyQ) diseases share common molecular pathogenic mechanisms involving mutant protein and RNA toxicity.
- Therapeutic strategies are advancing, with a focus on targeting gene expression early in disease pathogenesis.
Purpose of the Study:
- To review the use of oligonucleotide (ON)-based tools, including antisense oligonucleotides (ASOs) and RNA interference (RNAi) triggers, for treating polyQ diseases.
- To compare different gene silencing strategies (non-allele-selective and allele-selective) in cellular and animal models.
Main Methods:
- Review of studies utilizing ASOs and RNAi triggers for experimental treatment of polyQ diseases.
- Analysis of allele-selective strategies targeting SNPs or expanded CAG repeats.
- Comparison of gene silencing effectors based on design, efficiency in cell culture, and preclinical testing.
Main Results:
- Oligonucleotide-based tools are effective in reducing mutant gene expression in preclinical models of polyQ diseases.
- Both non-allele-selective and allele-selective silencing strategies have been explored.
- Allele-selective approaches offer potential for greater specificity by targeting specific mutations or repeat expansions.
Conclusions:
- ON-based gene silencing represents a promising therapeutic avenue for polyQ diseases.
- Further research is needed to optimize ON design, delivery, and efficacy, and to address current limitations for clinical translation.
