Antisense oligonucleotide therapeutics in neurodegenerative diseases: the case of polyglutamine disorders

Abstract

Polyglutamine (polyQ) disorders are a group of nine neurodegenerative diseases that share a common genetic cause, which is an expansion of CAG repeats in the coding region of the causative genes that are otherwise unrelated. The trinucleotide expansion encodes for an expanded polyQ tract in the respective proteins, resulting in toxic gain-of-function and eventually in neurodegeneration. Currently, no disease-modifying therapies are available for this group of disorders. Nevertheless, given their monogenic nature, polyQ disorders are ideal candidates for therapies that target specifically the gene transcripts. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. ASOs are small synthetic single-stranded chains of nucleic acids that target specific RNA transcripts through several mechanisms. ASOs can reduce the levels of mutant proteins by breaking down the targeted transcript, inhibit mRNA translation or alter the maturation of the pre-mRNA via splicing correction. Over the years, chemical optimization of ASO molecules has allowed significant improvement of their pharmacological properties, which has in turn made this class of therapeutics a very promising strategy to treat a variety of neurodegenerative diseases. Indeed, preclinical and clinical strategies have been developed in recent years for some polyQ disorders using ASO therapeutics. The success of ASOs in several animal models, as well as encouraging results in the clinic for Huntington’s disease, points towards a promising future regarding the application of ASO-based therapies for polyQ disorders in humans, offering new opportunities to address unmet medical needs for this class of disorders. This review aims to present a brief overview of key chemical modifications, mechanisms of action and routes of administration that have been described for ASO-based therapies. Moreover, it presents a review of the most recent and relevant preclinical and clinical trials that have tested ASO therapeutics in polyQ disorders.

CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

“…Studies reported that knockdown of both mATXN3 and wtATXN3 alleles using RNAi and ASO, were a doubleedged sword to SCA3/MJD models. Therefore, strategies aimed at selective silencing mutant alleles are developing rapidly [10,15,18,19,52]. In this study, we delivered paired sgRNA/Cas9n and donor DNA as modi cation templates to achieve HR repair, which was consistent with previous HD studies [24,25,53].…”

“…This strategy provided a valuable model for further investigating molecular mechanisms of SCA3/MJD. In previous studies, deleting the CAG expansions was the main method to silence mATXN3 [13,18,26,27]. More recently, the CRISPR/Cas9 system has been used to permanently clear the CAG expansions in exon 10 of ATXN3 using paired sgRNAs/Cas9n.…”

“…RNA interference (RNAi) inhibits gene expression by targeting the mRNA, which subsequently induce offtargeted sites (OTs) and degrade over time [10,11]. Antisense oligonucleotide (ASO) deletes trinucleotide expansions, via non-selective-alleles (both wild type and mutant alleles) silencing ATXN3 or HTT, is another effective strategy to cure polyQ diseases [12][13][14][15][16][17][18][19]. Although the non-selective strategy can effectively improve the neuropathological changes and motor function in HD mice, the safety risk of its application in humans cannot be excluded [19].…”

New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

“…These huntingtin-lowering approaches are a welcome addition and hopefully they will prove safe and efficacious for HD patients. In principal, the protein-lowering approach could be used to reduce other expanded polyQ proteins that cause additional diseases [ 111 ]. An obvious drawback is that individual ASOs must be designed and tested for each disease.…”

Genselektive Therapieansätze bei der Huntington-Krankheit

“…ASO-Therapeutika stellen eine neue Klasse von Substanzen dar, die eine wirksame und effiziente Modulation der Genexpression in vivo ermöglichen [16]. ASOs binden entsprechend des Watson-Crick-Basenpaarungsprinzips an die komplementären Sequenzen der Prä-mRNA und mRNA und führen -präferenziell über RNaseH1 im nukleären Kompartimentzu einem Abbau von HTT-Transkripten [17,18]. Da ASOs die Blut-Hirn-Schranke nicht passieren können, müssen sie intrathekal verabreicht werden.…”