The Yin and Yang of nucleic acid-based therapy in the brain. (August 2017)

• Record Type: Journal Article
• Authors: Gustincich, Stefano; Zucchelli, Silvia; Mallamaci, Antonello
• Is Part Of: Progress in neurobiology. Volume 155(2017:Aug.)
• Page Start: 194
• Page End: 211
• Publication Date: 2017-08
• Subjects: 3C chromosomal conformation capture -- AAV adeno-associated virus -- AD Alzheimer's disease -- Ago2 argonaute2 -- ALS amyotrophic lateral sclerosis -- AntagoNATs antagonist of natural antisense transcript -- APP amyloid precursor protein -- ASOs antisense oligonucleotides -- Aub aubergine -- BACE1 β-amyloid precursor protein cleaving enzyme 1 -- BBB blood brain barrier -- BD binding domain -- BDNF brain-derived neurotrophic factor -- Cas9 CRISPR-associated protein 9 -- CCPG1 cell cycle progression 1 -- CCR4 chemokine (C-C motif) receptor 4 -- COX2 cyclooxygenase 2 -- CRISPR clustered regularly interspaced short palindromic repeats -- CSDC2 cold shock domain containing C2, RNA binding -- CSF cerebrospinal fluid -- DHX9 DEAH (Asp-Glu-Ala-His) box helicase 9 -- ED effector domain -- Emx2 empty spiracles homeobox 2 -- eRNA enhancer RNA -- Foxg1 forkhead box G1 -- FRDA friedreich's ataxia -- FTD frontotemporal dementia -- FXN Frataxin -- GFP green fluorescent protein -- GOI gene-of-interest -- HD Huntington's disease -- HTT huntingtin gene -- IGF2 insulin-like growth factor 2 -- IL24 interleukin24 -- IL32 interleukin32 -- iPSC induced pluripotent stem cells -- LDLR low density lipoprotein receptor -- lincRNAs long intergenic non-coding RNAs -- LINE long interspersed nuclear element -- lncRNAs long non-coding RNAs -- miRNAs microRNAs -- NAT natural antisense transcript -- NMHVs nuclear localization signal-MS2 coat protein RNA interacting domain- -- HA epitope (3x)VP16 transactivating domain -- PABP poly(A)-binding protein -- PD Parkinson's disease -- piRNAs piwi-interacting RNAs -- bPLA2G4A phospholipase A2 -- polyA polyadenylated -- PR progesterone receptor -- PSEN1 presenilin 1 -- RAN repeat-associated non-ATG -- RAPGEF3 rap guanine nucleotide exchange factor (GEF) 3 -- RIP RNA immunoprecipitation -- RISCs RNA-instructed silencing complexes -- RNAa RNA activation -- RNAi RNA interference -- S/AS sense/antisense pairs -- saRNA small activator RNA -- SHANK2 SH3 and multiple ankyrin repeat domains 2 -- shRNA small hairpin RNA -- SINE short interspersed nuclear element -- SINEUP SINEB2 sequence to UP-regulate translation -- siRNAs small interfering RNAs -- SLC39A solute carrier family 39 -- SMA spinal muscular atrophy -- SMN survival of motor neuron -- SOD1 superoxide dismutase 1 -- SYNGAP1 synaptic ras GTPase activating protein 1 -- TEs transposable elements -- TFs transcription factors -- TGS transcriptional gene silencing -- TSS transcription start site -- UBE3A ubiquitin protein ligase E3A -- Uchl1 ubiquitin carboxyl-terminal esterase L1 -- UTR untranslated region -- VEGF vascular endothelial growth factor -- wt wild type; Nucleic-acid therapy -- Brain -- Neurodegenerative disease -- Non-coding RNA -- Small inhibitory RNA -- Antisense oligonucleotide -- RNA activation -- NMHV -- SINEUP; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2016.11.001
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: We introduce our current understanding on the functional output of the mammalian genome, paying special attention to long non-coding RNAs and their potential applications in molecular therapy. We discuss the challenges for the molecular therapy in the brain and we highlight the renaissance of nucleic acid-based drugs to treat neurodegenerative diseases. We describe the potential therapeutic effects that can be obtained by inhibiting (Yin) and increasing (Yang) gene expression. The Yin side of nucleic acid-based therapy: we summarize the current technologies and we provide examples of their applications to treat to neurodegenerative diseases in mouse models and in clinical trials. The Yang side of nucleic acid-based therapy: we discuss the molecular basis of new classes of activatory RNA-based drugs, acting at the transcriptional (saRNAs and NMHVs) and translational (SINEUPs) levels. We provide examples of activatory RNA therapy in neurodegenerative disorders in mouse models and in clinical trials. We conclude with our vision on the future perspectives of nucleic acid-based therapy in the brain. Abstract: The post-genomic era has unveiled the existence of a large repertory of non-coding RNAs and repetitive elements that play a fundamental role in cellular homeostasis and dysfunction. These may represent unprecedented opportunities to modify gene expression at the right time in the correct space in vivo, providing an almost unlimited reservoir of new potential pharmacological agents. Hijacking their mode of actions, the druggable genome can be extended to regulatory RNAs and DNA elements in a scalable fashion. Here, we discuss the state-of-the–art of nucleic acid-based drugs to treat neurodegenerative diseases. Beneficial effects can be obtained by inhibiting (Yin) and increasing (Yang) gene expression, depending on the disease and the drug target. Together with the description of the current use of inhibitory RNAs (small inhibitory RNAs and antisense oligonucleotides) in animal models and clinical trials, we discuss the molecular basis and applications of new classes of activatory RNAs at transcriptional (RNAa) and translational (SINEUP) levels.