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13 HD Insights, Vol. 13 Copyright © Huntington Study Group 2016. All rights reserved. H D I N S I G H T S This summer, Ionis Pharmaceuticals (formerly Isis Pharmaceuticals), in collaboration with the CHDI Foundation and Roche Pharmaceuticals, began a Phase I trial of the antisense oligonucleotide (ASO) IONIS-HTT Rx in Canada and Europe. The trial, named "Safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS-HTT Rx in patients with early manifest Huntington's disease," uses a randomized, placebo-controlled, double-blind design to evaluate the safety and tolerability of ascending doses of IONIS-HTT Rx . Both the active drug and placebo are administered intrathecally at four-week intervals over a 13-week treatment period. 3 If successful in this and subsequent trials, the compound could become the first disease-modifying drug for HD on the market. Gene silencing therapies for HD have long been a promising avenue of exploration. Nucleotide-based gene silencing methods have advanced considerably in recent years, and IONIS-HTT Rx is the first tested in human HD patients. By attacking HD near its genetic roots, the drug could potentially reduce, partly reverse, or even prevent the symptoms of HD. Numerous successes have been reported in rodent models, first with RNA-based compounds, 4 and more recently with ASOs. 5 ASOs are synthetic, modified nucleotide agents designed to bind to a chosen sequence in mRNA using Watson-Crick complementarity. Once bound, several cellular mRNA disposal mechanisms remove the mRNA, repressing gene expression by reducing translation and protein expression. 6 ASO-bound mRNA is degraded by RNAse H prior to splicing and nuclear export (see Figure). 7 Most trials in animal models have focused on nonselective silencing of both wild-type and mutant HTT alleles, though research into allele- selective approaches has also been undertaken. 5,8 Directly infused into the brain parenchyma or ventricles of HD-model mice, ASOs appear to significantly reduce mRNA expression and total HTT levels. This has been associated with both slowing of the phenotypic progression of HD, and substantial improvement in some manifestations that have clinically significant counterparts in human HD. 2 The effect of lowering wild-type HTT in humans remains unknown. Though the function of wild-type HTT is not understood, knocking out the gene is lethal to embryos in murine models, 9 and conditional HTT knockout has been reported to produce neurodegeneration. 10 However, using ASOs to knockdown 75% of total huntingtin in BACHD mice produced no detectable behavioral or motor deficits (though subtler effects may not be detectable in murine studies.) 11 The benefits of lowering the pathogenic mHTT protein may significantly outweigh the potential side effects of lowering the wild-type protein. 2 By: Priya Hays, PhD MANUFACTURER: Ionis Pharmaceuticals MOLECULAR STRUCTURE: DNA-based antisense oligonucleotide targeting huntingtin messenger RNA MECHANISM OF ACTION: ASOs bind messenger RNA to prevent translation and promote degradation by various cellular mechanisms. MEET THE COMPOUND: IONIS-HTT Rx Figure: "Schematic illustration of the three main approaches to lowering huntingtin expression. Zinc finger protein therapeutics aim to reduce transcription of the huntingtin gene. Translational repression can be attempted at the pre-mRNA level using DNA-based antisense oligonucleotides (ASOs) or on mature mRNA using short interfering RNA (siRNA) compounds. Different cellular mechanisms degrade the bound mRNA. 1 " (Figure and caption from Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington's disease: What's in the pipeline? Mov Disord. 2014 Sep 15; 29(11): 1434– 1445. Published under a Creative Commons Attribution License.) 2 1 Bennett CF, Swayze EE. RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform. Annu. Rev. Pharmacol. Toxicol. 2010;50(1):259-293. 2 Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington's disease: What's in the pipeline? Mov. Disord. 2014;29(11):1434-1445. 3 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS-HTTRx in Patients With Early Manifest Huntington's Disease [NCT02519036]. 2015. https://clinicaltrials.gov/ct2/show/NCT02519036. 4 Yu D, Pendergraff H, Liu J, et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012;150(5):895-908. doi: 10.1016/j.cell.2012.08.002. 5 Carroll JB, Warby SC, Southwell AL, et al. Potent and Selective Antisense Oligonucleotides Targeting Single-Nucleotide Polymorphisms in the Huntington Disease Gene / Allele-Specific Silencing of Mutant Huntingtin. Mol. Ther. 2011;19(12):2178-85. doi: 10.1038/mt.2011.201. Epub 2011 Oct 4. 6 Magen I, Hornstein E. Oligonucleotide-based therapy for neurodegenerative diseases. Brain Res. 2014;1584:116-128. 7 Martínez T, Wright N, López-Fraga M, et al. Silencing human genetic diseases with oligonucleotide-based therapies. Hum. Genet. 2013;132(5):481-493. 8 Kay C, Collins JA, Skotte NH, et al. Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry. Mol. Ther. 2015;23(11):1759-1771. 9 Nasir J, Floresco SB, O'Kusky JR, et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995;81(5):811-823. 10 Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 2000;26(3):300-306. 11 Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al. Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis. Neuron. 2012;74(6):1031-1044. Due to the inadequate identification of extensive direct quotations, this article has been withdrawn by the editors as of May 4, 2016.