Background. Expanded trinucleotide repeats cause Huntington's Disease (HD) and other degenerative disorders. There are no cures for these devastating illnesses and treatments are urgently needed. Trinucleotide repeat disorders are due to mutations in just one gene, and agents that block expression of the mutant gene offer a promising option for treatment. Antisense oligonucleotides (ASOs) or duplex RNAs can inhibit expression of trinucleotide repeat genes in animal models, but inhibition of both the mutant and wild-type alleles may not be tolerated in patients. Selective inhibition of only the mutant protein would be ideal, but requires innovative approaches to gene silencing because of the need to discriminate between the two similar alleles. During the previous funding period we used single-stranded antisense oligonucleotides, single-stranded interfering RNAs (ssiRNAs), and duplex RNAs to achieve selective inhibition of mutant HTT. Objective. We propose to maximize the potential for clinical development by optimizing these newly discovered compounds and better understanding their mechanisms of action. We will extend our strategy to other trinucleotide-repeat diseases to identify additional therapeutic lead molecules. The mRNAs of trinucleotide repeat genes differ in many ways, and the challenge of inhibitor development will lead to insights into how repetitive sequence affects the mechanism of recognition. At the most fundamental level, the chemical properties and design features of the nucleic acids we use are novel and their study will offer important general insights into gene silencing by ASOs, ssRNAs, and duplex RNAs.
Aim 1. Optimize potency and selectivity of duplex RNAs, ASOs, and ssRNAs. We will design and test new generations of compounds and assay their inhibition of HTT expression. The structure activity relationships we develop will allow us to select the best compounds for animal studies and offer mechanistic insights into allele-selectivity.
Aim 2. Investigate the mechanism of allele-selective inhibition. Understanding the mechanism of allele-selectivity will facilitate the design of highly effective inhibitors of HTT expression. We will us biochemical and cell-based approaches to characterize the protein- and nucleic acid- interactions that occur during recognition of HTT mRNA by our inhibitory molecules.
Aim 3. Application of inhibitors to other disease genes containing expanded repeats. Other disease genes contain expanded triplet repeats including ataxin-3, myotonic dystrophy protein kinase, and ataxin-7. Developing compounds to achieve allele-selective inhibition of these genes would widen the therapeutic potential of the approach and offer new perspective on mechanisms.

Public Health Relevance

Huntington's disease (HD) is an incurable neurodegenerative disorder. HD is caused by expression of mutant Huntington (HTT) protein, and an ideal therapeutic strategy would inhibit mutant HTT protein while leaving the wild-type protein untouched. My laboratory has developed three chemical strategies for selectively inhibiting production of the mutant protein. We propose to optimize inhibitors and understand how they function.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Fabian, Miles
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University of Texas Sw Medical Center Dallas
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Matsui, Masayuki; Corey, David R (2017) Non-coding RNAs as drug targets. Nat Rev Drug Discov 16:167-179
Matsui, Masayuki; Prakash, Thazha P; Corey, David R (2016) Argonaute 2-dependent Regulation of Gene Expression by Single-stranded miRNA Mimics. Mol Ther 24:946-55
Li, Liande; Matsui, Masayuki; Corey, David R (2016) Activating frataxin expression by repeat-targeted nucleic acids. Nat Commun 7:10606
Hu, Jiaxin; Liu, Jing; Li, Liande et al. (2015) Engineering Duplex RNAs for Challenging Targets: Recognition of GGGGCC/CCCCGG Repeats at the ALS/FTD C9orf72 Locus. Chem Biol 22:1505-1511
Chu, Yongjun; Wang, Tao; Dodd, David et al. (2015) Intramolecular circularization increases efficiency of RNA sequencing and enables CLIP-Seq of nuclear RNA from human cells. Nucleic Acids Res 43:e75
Gagnon, Keith T; Li, Liande; Chu, Yongjun et al. (2014) RNAi factors are present and active in human cell nuclei. Cell Rep 6:211-21
Matsui, Masayuki; Threlfall, Richard N; Caruthers, Marvin H et al. (2014) Effect of 2'-O-methyl/thiophosphonoacetate-modified antisense oligonucleotides on huntingtin expression in patient-derived cells. Artif DNA PNA XNA 5:e1146391
Gagnon, Keith T; Li, Liande; Janowski, Bethany A et al. (2014) Analysis of nuclear RNA interference in human cells by subcellular fractionation and Argonaute loading. Nat Protoc 9:2045-60
Liu, Jing; Yu, Dongbo; Aiba, Yuichiro et al. (2013) ss-siRNAs allele selectively inhibit ataxin-3 expression: multiple mechanisms for an alternative gene silencing strategy. Nucleic Acids Res 41:9570-83
Matsui, Masayuki; Prakash, Thazha P; Corey, David R (2013) Transcriptional silencing by single-stranded RNAs targeting a noncoding RNA that overlaps a gene promoter. ACS Chem Biol 8:122-6

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