Using non-coding small RNAs to develop therapies for Huntington's disease

Abstract

Huntington's disease (HD) is caused by an expansion of CAG triplets at the 5¢ end of the HD gene, which encodes a pathologically elongated polyglutamine stretch near the N-terminus of huntingtin. HD is an incurable autosomal-dominant neurodegenerative disease characterized by movement disorder, as well as emotional distress and dementia. The newly discovered roles of the non-coding small RNAs in specific degradation or translational suppression of the targeted mRNAs suggest a potential therapeutic approach of post-transcriptional gene silencing that targets the underlying disease etiology rather than the downstream pathological consequences. From pre-clinical trials in different HD animal models to cells from HD patients, small RNA interference has been applied to 'allele-non-specifically or allele-specifically' silence the mutant HD transgene or endogenous mutant HD allele. Silencing the mutant HD transgene significantly inhibits neurodegeneration, improves motor control, and extends survival of HD mice. With future improvement of mutant allele selectivity (preserving the expression of the neuroprotective wild-type allele), target specificity, efficacy and safety, as well as optimization of delivery methods, small non-coding RNA-based therapeutic applications will be a promising approach to treat HD.

Approches degene silencingpour le traitement de la maladie de Huntington

“…La plupart des approches à ce jour ne discriminent pas les deux transcrits de l'HTT et induisent une baisse partielle de l'expression des deux allèles (Figure 2). Récemment, des stratégies permettant la reconnaissance exclusive de la mHTT grâce à la longueur de l'expansion CAG ou à certains SNP ont conduit à un silencing allélique de la huntingtine mutée [18].…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…miRNAs, ss-siRNAs, and shRNAs can target either coding sequence (CDS) or the 3-untranslated region (UTR) of mthtt messenger RNA (mRNA). Consequently, they participate in mRNA degradation through Argounate (Ago) and the RNA-induced silencing complex (RISC)-dependent pathway [114,126] response to oxidative stress or DNA damage [113]. Interestingly, mithramycin action involves epigenetic compensation by reducing pericentromeric heterochromatin condensation, which ameliorates the clinical and neuropathological phenotype and extends survival of transgenic HD (R6/2) mice [56,66].…”

“…Because HD is caused by a mutation at exon1 of htt gene, gene therapy to eliminate the expression of lethal gene (mthtt) using ncRNAs has been proposed and actively investigated over the last few years [114]. Wild-type htt protein functions as a survival factor that is indispensable for neuronal function, while mthtt protein is neurotoxic.…”

“…The disruption of transcriptional homeostasis through DNA methylation, histone methylation/acetylation, and miRNA biogenesis is associated with a number of pathological mechanisms in HD. The use of noncoding small RNA-based therapy targeting mthtt in particular may be a successful therapeutic strategy [114]. Approaches using, noncoding small RNA-based therapeutic interventions need improved target specificity for the mthtt allele, efficacy, and region-specific delivery.…”

Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems

“…An siRNA knock-out of the mutated HD transgene significantly inhibits neurodegeneration, improves motor control, and extends survival of mice with HD. SiRNA could prove to be a promising therapy for HD, given that the siRNA can be made selective enough to target the mutant gene without preventing the expression of the its normal, wild-type allele counterpart [141].…”