Reduction of Off-Target Effects of Gapmer Antisense Oligonucleotides by Oligonucleotide Extension

Hidenori Yasuhara1, Tokuyuki Yoshida1, Kiyomi Sasaki2, Satoshi Obika1, Takao Inoué2
1Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
2Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan

Tóm tắt

Từ khóa


Tài liệu tham khảo

Yacyshyn B, Bowen-Yacyshyn MB, Shanahan W. The clinical experience of antisense therapy to ICAM-1 in Crohn’s disease. Curr Opin Mol Ther. 1999;1:332–5.

Crook ST. Antisense drug technology: principles, strategies, and applications. 2nd ed. CRC Press; 2008.

Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62:2178–84. https://doi.org/10.1016/j.jacc.2013.07.081.

Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:22–31. https://doi.org/10.1056/NEJMoa1716793.

Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019;31:531–42. https://doi.org/10.1056/NEJMoa1715944.

Kurreck J, Wyszko E, Gillen C, Erdmann VA. Design of antisense oligonucleotides stabilized by locked nucleic acids. Nucleic Acids Res. 2002;30:1911–8. https://doi.org/10.1093/nar/30.9.1911.

Geary RS. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2009;5:381–91. https://doi.org/10.1517/17425250902877680.

Bennett FC, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259–93. https://doi.org/10.1146/annurev.pharmtox.010909.105654.

Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;314: 314ra185. https://doi.org/10.1126/scitranslmed.aac5272.

Chowdhury S, Burris HA, Patel M, Infante JR, Jones SF, Voskoboynik M, et al. A phase I dose escalation, safety and pharmacokinetic (PK) study of AZD5312 (IONIS- ARRx), a first-in-class generation 2.5 antisense oligonucleotide targeting the androgen receptor (AR). Eur J Cancer. 2016;69:S145. https://doi.org/10.1186/s40425-018-0436-5.

Pfeiffer N, Voykov B, Renieri G, Bell K, Richter P, Weigel M, et al. First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-beta2), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery. PLoS ONE. 2017;12: e0188899. https://doi.org/10.1371/journal.pone.0188899.

Reilley MJ, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y, et al. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. J Immunother Cancer. 2018;6:119. https://doi.org/10.1186/s40425-018-0436-5.

Ribrag V, Lee ST, Rizzieri D, Dyer MJS, Fayad L, Kurzrock R, et al. A phase 1b study to evaluate the safety and efficacy of durvalumab in combination with tremelimumab or danvatirsen in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21:309–17. https://doi.org/10.1038/10.1016/j.clml.2020.12.012.

Burel SA, Hart CE, Cauntay P, Hsiao J, Machemer T, Katz M, et al. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts. Nucleic Acids Res. 2016;44:2093–109. https://doi.org/10.1093/nar/gkv1210.

Kasuya T, Hori S, Watanabe A, Nakajima M, Gahara Y, Rokushima M, et al. Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides. Sci Rep. 2016;6:30377. https://doi.org/10.1038/srep30377.

Lindow M, Vornlocher HP, Riley D, Kornbrust DJ, Burchard J, Whiteley LO, et al. Assessing unintended hybridization-induced biological effects of oligonucleotides. Nat Biotechnol. 2012;30:920–3. https://doi.org/10.1038/nbt.2376.

Yoshida T, Naito Y, Sasaki K, Uchida E, Sato Y, Naito M, et al. Estimated number of off-target candidate sites for antisense oligonucleotides in human mRNA sequences. Genes Cells. 2018;23:448–55. https://doi.org/10.1111/gtc.12587.

Yoshida T, Naito Y, Yasuhara H, Sasaki K, Kawaji H, Kawai J, et al. Evaluation of off-target effects of gapmer antisense oligonucleotides using human cells. Genes Cells. 2019;24:827–35. https://doi.org/10.1111/gtc.12730.

Shen W, Hoyos CLD, Migawa MT, Vickers TA, Sun H, Low A, et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat Biotechnol. 2019;37:640–50. https://doi.org/10.1038/s41587-019-0106-2.

Kamola PJ, Kitson JD, Turner G, Maratou K, Eriksson S, Panjwani A, et al. In silico and in vitro evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization. Nucleic Acids Res. 2015;43:8638–50. https://doi.org/10.1093/nar/gkv857.

Hagedorn PH, Hansen BR, Koch T, Lindow M. Managing the sequence-specificity of antisense oligonucleotides in drug discovery. Nucleic Acids Res. 2017;45:2262–82. https://doi.org/10.1016/0076-6879(95)46005-5.

Hagedorn PH, Pontoppidan M, Bisgaard TS, Berrera M, Dieckmann A, Ebeling M, et al. Identifying and avoiding off-target effects of RNase H-dependent antisense oligonucleotides in mice. Nucleic Acids Res. 2018;46:5366–80. https://doi.org/10.1093/nar/gky397.

Michel S, Schirduan K, Shen Y, Klar R, Tost J, Jaschinski F. Using RNA-seq to assess off-target effects of antisense oligonucleotides in human cell lines. Mol Diagn Ther. 2021;25:77–85. https://doi.org/10.1007/s40291-020-00504-4.

Gray DM, Hung SH, Johnson KH. Absorption and circular dichroism spectroscopy of nucleic acid duplexes and triplexes. Methods Enzymol. 1995;246:19–34. https://doi.org/10.1016/0076-6879(95)46005-5.

Stanton R, Sciabola S, Salatto C, Weng Y, Moshinsky D, Little J, et al. Chemical modification study of antisense gapmers. Nucleic Acid Ther. 2012;22:344–59. https://doi.org/10.1089/nat.2012.0366.

Cerritelli SM, Crouch RJ. Ribonuclease H: the enzymes in eukaryotes. FEBS J. 2009;276:1494–505. https://doi.org/10.1111/j.1742-4658.2009.06908.x.

Uppuladinne MVN, Sonavane UB, Deka RC, Joshi RR. Structural insight into antisense gapmer-RNA oligomer duplexes through molecular dynamics simulations. J Biomol Struct Dyn. 2019;37:2823–36. https://doi.org/10.1080/07391102.2018.1498390.

Magner D, Biala E, Lisowiec-Wachnicka J, Kierzek R. Influence of mismatched and bulged nucleotides on SNP-preferential RNase H cleavage of RNA-antisense gapmer heteroduplexes. Sci Rep. 2017;7:12532. https://doi.org/10.1038/s41598-017-12844-z.

Papargyri N, Pontoppidan M, Andersen MR, Koch T, Hagedorn PH. Chemical diversity of locked nucleic acid-modified antisense oligonucleotides allows optimization of pharmaceutical properties. Mol Ther Nucleic Acids. 2020;19:706–17. https://doi.org/10.1016/j.omtn.2019.12.011.

Dieckmann A, Hagedorn PH, Burki Y, Brugmann C, Berrera M, Ebeling M, et al. A sensitive in vitro approach to assess the hybridization-dependent toxic potential of high affinity gapmer oligonucleotides. Mol Ther Nucleic Acids. 2018;10:45–54. https://doi.org/10.1016/j.omtn.2017.11.004.

Frazier KS. Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol. 2015;43:78–89. https://doi.org/10.1177/0192623314551840.