Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Abstract

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

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].…”

“…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].…”

“…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]. However, speci c targeting single nucleotide polymorphism (SNPs) in mutant allele to achieve permanent gene silencing, and without affecting the normal allele, is the ultimate targets of treatment [20,21].…”

Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases

“…These strategies include the silencing of both HTT alleles in a non-allele-selective strategy and the targeting of single-nucleotide polymorphisms (SNPs) linked to repeat expansions. The repeat region itself may be targeted in an allele selective and non-selective manner (Fiszer et al, 2012 ; Keiser et al, 2016 ; Esteves et al, 2017 ). RNA interference and antisense oligonucleotide technologies, which have been used for many years in experimental therapy for polyQ diseases, are currently complemented with genome editing systems such as the CRISPR/Cas9 (Shin et al, 2016 ; Kolli et al, 2017 ; Merienne et al, 2017 ; Monteys et al, 2017 ; Yang et al, 2017 ).…”

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

“…Importantly, some of these strategies alleviate polyQ toxicity in the absence of severe off-target effects, suggesting that they warrant further exploration as therapeutic approaches for the broad treatment of polyQ disorders. These studies have spurred diverse therapeutic efforts which have been recently thoroughly reviewed (Esteves et al, 2016). The extensive evidence implicating the proteasome as a therapeutic target, as well as its dysfunction and mislocalization in polyQ diseases, highlight its importance in the pathophysiology of disease.…”