By: Meredith A. Achey, BM
Manufacturer: WAVE Life Sciences
Molecular formula: Stereopure antisense oligonucleotide (ASO) targeting single nucleotide polymorphisms (SNPs).
Mechanism of action: WVE-120101 and WVE-120102 act by selectively binding mHTT mRNA, thereby selectively inhibiting production of mHTT. WAVE Life Sciences has developed a strategy to synthesize stereopure nucleotide-based therapies that may improve their efficacy and safety.1
Nucleotide-based gene silencing therapies such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) represent some of the most promising potential therapies for genetic diseases such as HD. However, methods for their synthesis developed to date produce mixtures of stereoisomers, some of which are therapeutic, and others that may be less effective or potentially detrimental.1,2 WAVE Life Sciences has developed a propriety technology for the synthesis of stereopure nucleic acid therapeutics3-5 with the potential to improve therapeutic efficacy and reduce harmful effects.6
The company hopes to develop stereopure nucleic acid therapies for a variety of genetic diseases, including central nervous system disease such as HD, and a number of genetic disorders that affect other organ systems.7
WAVE’s most advanced HD programs currently encompass two compounds that target different single nucleotide polymorphisms (SNPs) common to the mutant allele. The company plans to file investigational new drug applications for both of these compounds this year, and has received orphan drug designation in the US for its lead candidate, WVE-120101.8 These compounds target the two most common SNPs associated with mHTT.9 Current efforts by Ionis in the first human trial of a gene-silencing nucleotide-based therapy do not target mHTT selectively (see HD Insights, Vol. 13), although preclinical data have not suggested a significant decrease in efficacy nor increase in potential harm from a non-selective approach.10 However, interest in more selective approaches has continued because the possibility for off-target effects with non-selective silencing remains problematic.11-15
Pfister and colleagues9 reported that they have been able to develop small interfering RNAs (siRNAs) that target specific SNPs to treat approximately 75% of individuals with HD. In 2015, targeting approaches were further refined with the discovery that targeting three common haplotypes could enable selective silencing of the HD gene in approximately 80% of patients.13 The use of stereopure synthesis to enhance the delivery and efficacy of these highly targeted compounds may further refine ongoing efforts to develop an effective and safe gene-silencing therapy for HD.
Table. Selected studies of allele-specific gene-silencing therapies
|Study||Year||Type of therapy||Most promising target SNP(s)||Summary|
|Skotte NH et al.16||2014||ASO||rs7685686_A||Allele-specific, high affinity ASOs targeting different SNPs associated with HD could together offer allele-selective silencing to approximately 50% of patients, and non-selective silencing to the remainder.|
|Drouet et al.12||2014||shRNA||rs363125, rs362331, rs2276881, rs362307||shRNA delivered with a lentiviral vector to cellular and animal models showed in vitro and in vivo silencing of mHTT.|
|Yu D et al.17||2012||ss-siRNA||Targets CAG repeat||ss-siRNA targeting expanded CAG repeats led to selective silencing of mHTT expression in an HD mouse model.|
|Abbreviations: ASO: Antisense oligonucleotide; shRNA: small hairpin RNA; ss-siRNA: single-stranded small interfering RNA; SNP: single nucleotide polymorphism|
1. 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):1434-45. doi: 10.1002/mds.26007. Epub 2014 Aug 25.
2. De Mesmaeker A, Altmann K-H, Waldner A, Wendeborn S. Backbone modifications in oligonucleotides and peptide nucleic acid systems. Curr. Opin. Struct. Biol. 1995;5(3):343-355.
3. Butler D, Iwamoto N, Meena M, et al. Chiral control. Google Patents; 2015.
4. Verdine GL, Meena M, Iwamoto N. Novel nucleic acid prodrugs and methods of use thereof. Google Patents; 2012.
5. Verdine GL, Meena M, Iwamoto N, Butler DCD. Methods for the synthesis of functionalized nucleic acids. Google Patents; 2014.
6. Wave Life Sciences. Wave Life Sciences – Platform. [Website]. 2016; www.wavelifesciences.com/platform. Accessed August 19, 2016.
7. Wave Life Sciences. Wave Life Science – Pipeline. 2016; www.wavelifesciences.com/pipeline. Accessed August 19, 2016.
8. WAVE Life Sciences receives orphan drug designation from FDA for its lead candidate designed to treat Huntington’s disease [press release]. June 21, 2016.
9. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 2009;19(9):774-778.
10. 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 Jun 21;74(6):1031-44. doi: 10.1016/j.neuron.2012.05.009.
11. 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 Dec;19(12):2178-85. doi: 10.1038/mt.2011.201. Epub 2011 Oct 4.
12. Drouet V, Ruiz M, Zala D, et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS One. 2014 Jun 13;9(6):e99341.
13. 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 Nov;23(11):1759-71.
14. Miniarikova J, Zanella I, Huseinovic A, et al. Design, characterization, and lead selection of therapeutic mirnas targeting huntingtin for development of gene therapy for Huntington’s disease. Mol Ther Nucleic Acids. 2016 Mar 22;5:e297.
15. Pfister EL, Kennington L, Straubhaar J, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr Biol. 2009 May 12;19(9):774-8.
16. Skotte NH, Southwell AL, Østergaard ME, et al. Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014 Sep 10;9(9):e107434.
17. Yu D, Pendergraff H, Liu J, et al. Single-stranded rnas use rnai to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012 Aug 31;150(5):895-908.