Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Factors Influencing ADME Properties of Therapeutic Antisense Oligonucleotides: Physicochemical Characteristics and Beyond

Author(s): Rongrong Jiang*, Shirin Hooshfar, Marsha Rebecca Eno, Cassandra Yun, Estevan Sonego Zimmermann and Raku Shinkyo*

Volume 24, Issue 7, 2023

Published on: 19 May, 2023

Page: [536 - 552] Pages: 17

DOI: 10.2174/1389200224666230418092626

Price: $65

conference banner
Abstract

Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution, metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore, thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar chemistry, conjugation approaches, sites and routes of administration, etc., are the principal determinants of ADME and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs. We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.

« Previous
Graphical Abstract

[1]
Rogers, H.; Adeniyi, O.; Ramamoorthy, A.; Bailey, S.; Pacanowski, M. Clinical Pharmacology studies supporting oligonucleotide therapy development: An assessment of therapies approved and in development between 2012 and 2018. Clin. Transl. Sci., 2021, 14(2), 468-475.
[http://dx.doi.org/10.1111/cts.12945] [PMID: 33278337]
[2]
Crooke, S.T.; Baker, B.F.; Crooke, R.M.; Liang, X. Antisense technology: An overview and prospectus. Nat. Rev. Drug Discov., 2021, 20(6), 427-453.
[http://dx.doi.org/10.1038/s41573-021-00162-z] [PMID: 33762737]
[3]
Shadid, M.; Badawi, M.; Abulrob, A. Antisense oligonucleotides: Absorption, distribution, metabolism, and excretion. Expert Opin. Drug Metab. Toxicol., 2021, 17(11), 1281-1292.
[http://dx.doi.org/10.1080/17425255.2021.1992382] [PMID: 34643122]
[4]
Gagliardi, M.; Ashizawa, A.T. The challenges and strategies of antisense oligonucleotide drug delivery. Biomedicines, 2021, 9(4), 433.
[http://dx.doi.org/10.3390/biomedicines9040433] [PMID: 33923688]
[5]
Kilanowska, A.; Studzińska, S. In vivo and in vitro studies of antisense oligonucleotides – a review. RSC Advances, 2020, 10(57), 34501-34516.
[http://dx.doi.org/10.1039/D0RA04978F] [PMID: 35514414]
[6]
Alhamadani, F.; Zhang, K.; Parikh, R.; Wu, H.; Rasmussen, T.P.; Bahal, R.; Zhong, X.; Manautou, J.E. Adverse drug reactions and toxicity of the food and drug administration–approved antisense oligonucleotide drugs. Drug Metab. Dispos., 2022, 50(6), 879-887.
[http://dx.doi.org/10.1124/dmd.121.000418] [PMID: 35221289]
[7]
Migliorati, J.M.; Liu, S.; Liu, A.; Gogate, A.; Nair, S.; Bahal, R.; Rasmussen, T.P.; Manautou, J.E.; Zhong, X. Absorption, distribution, metabolism, and excretion of us food and drug administration–approved antisense oligonucleotide drugs. Drug Metab. Dispos., 2022, 50(6), 888-897.
[http://dx.doi.org/10.1124/dmd.121.000417] [PMID: 35221287]
[8]
Gennemark, P.; Walter, K.; Clemmensen, N.; Rekić, D.; Nilsson, C.A.M.; Knöchel, J.; Hölttä, M.; Wernevik, L.; Rosengren, B.; Kakol-Palm, D.; Wang, Y.; Yu, R.Z.; Geary, R.S.; Riney, S.J.; Monia, B.P.; Isaksson, R.; Jansson-Löfmark, R.; Rocha, C.S.J.; Lindén, D.; Hurt-Camejo, E.; Crooke, R.; Tillman, L.; Rydén-Bergsten, T.; Carlsson, B.; Andersson, U.; Elebring, M.; Tivesten, A.; Davies, N. An oral anti-sense oligonucleotide for PCSK9 inhibition. Sci. Transl. Med., 2021, 13(593), eabe9117.
[http://dx.doi.org/10.1126/scitranslmed.abe9117] [PMID: 33980578]
[9]
Khvorova, A.; Watts, J.K. The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol., 2017, 35(3), 238-248.
[http://dx.doi.org/10.1038/nbt.3765] [PMID: 28244990]
[10]
Winkler, J.; Stessl, M.; Amartey, J.; Noe, C.R. Off-target effects related to the phosphorothioate modification of nucleic acids. ChemMedChem, 2010, 5(8), 1344-1352.
[http://dx.doi.org/10.1002/cmdc.201000156] [PMID: 20544786]
[11]
Knouse, K.W.; deGruyter, J.N.; Schmidt, M.A.; Zheng, B.; Vantourout, J.C.; Kingston, C.; Mercer, S.E.; Mcdonald, I.M.; Olson, R.E.; Zhu, Y.; Hang, C.; Zhu, J.; Yuan, C.; Wang, Q.; Park, P.; Eastgate, M.D.; Baran, P.S.; Unlocking, P. V): Reagents for chiral phosphorothioate syn-thesis. Science, 2018, 361(6408), 1234-1238.
[http://dx.doi.org/10.1126/science.aau3369] [PMID: 30072577]
[12]
Dirin, M.; Winkler, J. Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleo-tides. Expert Opin. Biol. Ther., 2013, 13(6), 875-888.
[http://dx.doi.org/10.1517/14712598.2013.774366] [PMID: 23451977]
[13]
Shen, W.; De Hoyos, C.L.; Migawa, M.T.; Vickers, T.A.; Sun, H.; Low, A.; Bell, T.A., III; Rahdar, M.; Mukhopadhyay, S.; Hart, C.E.; Bell, M.; Riney, S.; Murray, S.F.; Greenlee, S.; Crooke, R.M.; Liang, X.; Seth, P.P.; Crooke, S.T. Chemical modification of PS-ASO thera-peutics reduces cellular protein-binding and improves the therapeutic index. Nat. Biotechnol., 2019, 37(6), 640-650.
[http://dx.doi.org/10.1038/s41587-019-0106-2] [PMID: 31036929]
[14]
Crooke, S.T.; Liang, X.; Crooke, R.M.; Baker, B.F.; Geary, R.S. Antisense drug discovery and development technology considered in a pharmacological context. Biochem. Pharmacol., 2021, •••, 189114196.
[http://dx.doi.org/10.1016/j.bcp.2020.114196] [PMID: 32800852]
[15]
Chan, L.; Yokota, T. Development and clinical applications of antisense oligonucleotide gapmers. Methods Mol. Biol., 2020, 2176, 21-47.
[http://dx.doi.org/10.1007/978-1-0716-0771-8_2] [PMID: 32865780]
[16]
Seth, P.P.; Siwkowski, A.; Allerson, C.R.; Vasquez, G.; Lee, S.; Prakash, T.P.; Kinberger, G.; Migawa, M.T.; Gaus, H.; Bhat, B.; Swayze, E.E. Design, synthesis and evaluation of constrained methoxyethyl (cMOE) and constrained ethyl (cEt) nucleoside analogs. Nucleic Acids Symp. Ser., 2008, 52(1), 553-554.
[http://dx.doi.org/10.1093/nass/nrn280] [PMID: 18776499]
[17]
Seth, P.P.; Siwkowski, A.; Allerson, C.R.; Vasquez, G.; Lee, S.; Prakash, T.P.; Wancewicz, E.V.; Witchell, D.; Swayze, E.E. Short antisense oligonucleotides with novel 2′-4′ conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. J. Med. Chem., 2009, 52(1), 10-13.
[http://dx.doi.org/10.1021/jm801294h] [PMID: 19086780]
[18]
Vickers, T.A.; Crooke, S.T. Development of a quantitative bret affinity assay for nucleic acid-protein interactions. PLoS One, 2016, 11(8), e0161930.
[http://dx.doi.org/10.1371/journal.pone.0161930] [PMID: 27571227]
[19]
Crooke, S.T.; Wang, S.; Vickers, T.A.; Shen, W.; Liang, X. Cellular uptake and trafficking of antisense oligonucleotides. Nat. Biotechnol., 2017, 35(3), 230-237.
[http://dx.doi.org/10.1038/nbt.3779] [PMID: 28244996]
[20]
Juliano, R.L.; Carver, K. Cellular uptake and intracellular trafficking of oligonucleotides. Adv. Drug Deliv. Rev., 2015, 87, 35-45.
[http://dx.doi.org/10.1016/j.addr.2015.04.005] [PMID: 25881722]
[21]
Juliano, R.L.; Ming, X.; Nakagawa, O. Cellular uptake and intracellular trafficking of antisense and siRNA oligonucleotides. Bioconjug. Chem., 2012, 23(2), 147-157.
[http://dx.doi.org/10.1021/bc200377d] [PMID: 21992697]
[22]
Gaus, H.J.; Gupta, R.; Chappell, A.E.; Østergaard, M.E.; Swayze, E.E.; Seth, P.P. Characterization of the interactions of chemically-modified therapeutic nucleic acids with plasma proteins using a fluorescence polarization assay. Nucleic Acids Res., 2019, 47(3), 1110-1122.
[http://dx.doi.org/10.1093/nar/gky1260] [PMID: 30566688]
[23]
Arora, V.; Devi, G.; Iversen, P. Neutrally charged phosphorodiamidate morpholino antisense oligomers: Uptake, efficacy and pharmaco-kinetics. Curr. Pharm. Biotechnol., 2004, 5(5), 431-439.
[http://dx.doi.org/10.2174/1389201043376706] [PMID: 15544491]
[24]
Iversen, P.; Aird, K.; Wu, R.; Morse, M.; Devi, G. Cellular uptake of neutral phosphorodiamidate morpholino oligomers. Curr. Pharm. Biotechnol., 2009, 10(6), 579-588.
[http://dx.doi.org/10.2174/138920109789069279] [PMID: 19619124]
[25]
Sheng, L.; Rigo, F.; Bennett, C.F.; Krainer, A.R.; Hua, Y. Comparison of the efficacy of MOE and PMO modifications of systemic anti-sense oligonucleotides in a severe SMA mouse model. Nucleic Acids Res., 2020, 48(6), 2853-2865.
[http://dx.doi.org/10.1093/nar/gkaa126] [PMID: 32103257]
[26]
Chen, J.C.J.; King, O.D.; Zhang, Y.; Clayton, N.P.; Spencer, C.; Wentworth, B.M.; Emerson, C.P., Jr; Wagner, K.R. Morpholino-mediated knockdown of dux4 toward facioscapulohumeral muscular dystrophy therapeutics. Mol. Ther., 2016, 24(8), 1405-1411.
[http://dx.doi.org/10.1038/mt.2016.111] [PMID: 27378237]
[27]
Arora, V.; Cate, M.L.; Ghosh, C.; Iversen, P.L. Phosphorodiamidate morpholino antisense oligomers inhibit expression of human cyto-chrome P450 3A4 and alter selected drug metabolism. Drug Metab. Dispos., 2002, 30(7), 757-762.
[http://dx.doi.org/10.1124/dmd.30.7.757] [PMID: 12065433]
[28]
Taylor, M.F.; Paulauskis, J.D.; Weller, D.D.; Kobzik, L. Comparison of efficacy of antisense oligomers directed toward tnf-α in helper t and macrophage cell lines. Cytokine, 1997, 9(9), 672-681.
[http://dx.doi.org/10.1006/cyto.1997.0212] [PMID: 9325016]
[29]
Laktionov, P.P.; Dazard, J.E.; Vives, E.; Rykova, E.Y.; Piette, J.; Vlassov, V.V.; Lebleu, B. Characterisation of membrane oligonucleotide-binding proteins and oligonucleotide uptake in keratinocytes. Nucleic Acids Res., 1999, 27(11), 2315-2324.
[http://dx.doi.org/10.1093/nar/27.11.2315] [PMID: 10325420]
[30]
Geary, R.S.; Norris, D.; Yu, R.; Bennett, C.F. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv. Drug Deliv. Rev., 2015, 87, 46-51.
[http://dx.doi.org/10.1016/j.addr.2015.01.008] [PMID: 25666165]
[31]
Yu, R.Z.; Kim, T.W.; Hong, A.; Watanabe, T.A.; Gaus, H.J.; Geary, R.S. Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab. Dispos., 2007, 35(3), 460-468.
[http://dx.doi.org/10.1124/dmd.106.012401] [PMID: 17172312]
[32]
Geary, R.S. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin. Drug Metab. Toxicol., 2009, 5(4), 381-391.
[http://dx.doi.org/10.1517/17425250902877680] [PMID: 19379126]
[33]
Graham, M.J.; Crooke, S.T.; Lemonidis, K.M.; Gaus, H.J.; Templin, M.V.; Crooke, R.M. Hepatic distribution of a phosphorothioate oli-godeoxynucleotide within rodents following intravenous administration212Abbreviations: HSV, herpes simplex virus; CGE, capillary gel electrophoresis; and HPLC/ES-MS, high performance liquid chromatography/electrospray-mass spectrometry.1Johnston J, ISIS Pharma-ceuticals, personal communication. Cited with permission. Biochem. Pharmacol., 2001, 62(3), 297-306.
[http://dx.doi.org/10.1016/S0006-2952(01)00669-4] [PMID: 11434902]
[34]
Graham, M.J.; Crooke, S.T.; Monteith, D.K.; Cooper, S.R.; Lemonidis, K.M.; Stecker, K.K.; Martin, M.J.; Crooke, R.M. In vivo distribu-tion and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration. J. Pharmacol. Exp. Ther., 1998, 286(1), 447-458.
[PMID: 9655890]
[35]
Iwazaki, N.; Kodaira, H.; Goto, A.; Yamanaka, Y. Current status of pharmacokinetic assessment for antisense oligonucleotide therapeutics. Pharma. Med. Device Regulatory Sci., 2021, 52(3), 150-163.
[36]
McMahon, B.M.; Mays, D.; Lipsky, J.; Stewart, J.A.; Fauq, A.; Richelson, E. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev., 2002, 12(2), 65-70.
[http://dx.doi.org/10.1089/108729002760070803] [PMID: 12074366]
[37]
Thompson, J.D.; Kornbrust, D.J.; Foy, J.W.D.; Solano, E.C.R.; Schneider, D.J.; Feinstein, E.; Molitoris, B.A.; Erlich, S. Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. Nucleic Acid Ther., 2012, 22(4), 255-264.
[http://dx.doi.org/10.1089/nat.2012.0371] [PMID: 22913596]
[38]
Crooke, S.T.; Vickers, T.A.; Liang, X. Phosphorothioate modified oligonucleotide–protein interactions. Nucleic Acids Res., 2020, 48(10), 5235-5253.
[http://dx.doi.org/10.1093/nar/gkaa299] [PMID: 32356888]
[39]
Zhao, X.; Pan, F.; Holt, C.M.; Lewis, A.L.; Lu, J.R. Controlled delivery of antisense oligonucleotides: A brief review of current strategies. Expert Opin. Drug Deliv., 2009, 6(7), 673-686.
[http://dx.doi.org/10.1517/17425240902992894] [PMID: 19552611]
[40]
Benizri, S.; Gissot, A.; Martin, A.; Vialet, B.; Grinstaff, M.W.; Barthélémy, P. Bioconjugated oligonucleotides: Recent developments and therapeutic applications. Bioconjug. Chem., 2019, 30(2), 366-383.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00761] [PMID: 30608140]
[41]
Wang, S.; Allen, N.; Prakash, T.P.; Liang, X-h.; Crooke, S.T. Lipid conjugates enhance endosomal release of antisense oligonucleotides into cells. Nucleic Acid Ther., 2019, 29(5), 245-255.
[42]
Chappell, A.E.; Gaus, H.J.; Berdeja, A.; Gupta, R.; Jo, M.; Prakash, T.P.; Oestergaard, M.; Swayze, E.E.; Seth, P.P. Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice. Nucleic Acids Res., 2020, 48(8), 4382-4395.
[http://dx.doi.org/10.1093/nar/gkaa164] [PMID: 32182359]
[43]
Prakash, T.P.; Graham, M.J.; Yu, J.; Carty, R.; Low, A.; Chappell, A.; Schmidt, K.; Zhao, C.; Aghajan, M.; Murray, H.F.; Riney, S.; Booten, S.L.; Murray, S.F.; Gaus, H.; Crosby, J.; Lima, W.F.; Guo, S.; Monia, B.P.; Swayze, E.E.; Seth, P.P. Targeted delivery of antisense oligo-nucleotides to hepatocytes using triantennary N -acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res., 2014, 42(13), 8796-8807.
[http://dx.doi.org/10.1093/nar/gku531] [PMID: 24992960]
[44]
Tardif, J.C.; Karwatowska-Prokopczuk, E.; Amour, E.S.; Ballantyne, C.M.; Shapiro, M.D.; Moriarty, P.M.; Baum, S.J.; Hurh, E.; Bartlett, V.J.; Kingsbury, J.; Figueroa, A.L.; Alexander, V.J.; Tami, J.; Witztum, J.L.; Geary, R.S.; O’Dea, L.S.L.; Tsimikas, S.; Gaudet, D. Apolipo-protein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur. Heart J., 2022, 43(14), 1401-1412.
[http://dx.doi.org/10.1093/eurheartj/ehab820] [PMID: 35025993]
[45]
McClorey, G.; Banerjee, S. Cell-penetrating peptides to enhance delivery of oligonucleotide-based therapeutics. Biomedicines, 2018, 6(2), 51.
[http://dx.doi.org/10.3390/biomedicines6020051] [PMID: 29734750]
[46]
Midoux, P.; Pichon, C.; Yaouanc, J.J.; Jaffrès, P.A. Chemical vectors for gene delivery: A current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. Br. J. Pharmacol., 2009, 157(2), 166-178.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00288.x] [PMID: 19459843]
[47]
Betts, C.; Saleh, A.F.; Arzumanov, A.A.; Hammond, S.M.; Godfrey, C.; Coursindel, T.; Gait, M.J.; Wood, M.J.A. Pip6-PMO, a new genera-tion of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for dmd treatment. Mol. Ther. Nucleic Acids, 2012, 1(8), e38.
[http://dx.doi.org/10.1038/mtna.2012.30] [PMID: 23344180]
[48]
Albertshofer, K.; Siwkowski, A.M.; Wancewicz, E.V.; Esau, C.C.; Watanabe, T.; Nishihara, K.C.; Kinberger, G.A.; Malik, L.; Eldrup, A.B.; Manoharan, M.; Geary, R.S.; Monia, B.P.; Swayze, E.E.; Griffey, R.H.; Bennett, C.F.; Maier, M.A. Structure-activity relationship study on a simple cationic peptide motif for cellular delivery of antisense peptide nucleic acid. J. Med. Chem., 2005, 48(21), 6741-6749.
[http://dx.doi.org/10.1021/jm050490b] [PMID: 16220989]
[49]
Saar, K.; Lindgren, M.; Hansen, M.; Eiríksdóttir, E.; Jiang, Y.; Rosenthal-Aizman, K.; Sassian, M.; Langel, Ü. Cell-penetrating peptides: A comparative membrane toxicity study. Anal. Biochem., 2005, 345(1), 55-65.
[http://dx.doi.org/10.1016/j.ab.2005.07.033] [PMID: 16137634]
[50]
Knerr, L.; Prakash, T.P.; Lee, R.; Drury, W.J., III; Nikan, M.; Fu, W.; Pirie, E.; Maria, L.D.; Valeur, E.; Hayen, A.; Ölwegård-Halvarsson, M.; Broddefalk, J.; Ämmälä, C.; Østergaard, M.E.; Meuller, J.; Sundström, L.; Andersson, P.; Janzén, D.; Jansson-Löfmark, R.; Seth, P.P.; Andersson, S. Glucagon like peptide 1 receptor agonists for targeted delivery of antisense oligonucleotides to pancreatic beta cell. J. Am. Chem. Soc., 2021, 143(9), 3416-3429.
[http://dx.doi.org/10.1021/jacs.0c12043] [PMID: 33626278]
[51]
Mullard, A. Antibody–oligonucleotide conjugates enter the clinic. Nat. Rev. Drug Discov., 2022, 21(1), 6-8.
[http://dx.doi.org/10.1038/d41573-021-00213-5] [PMID: 34903879]
[52]
Hammond, S.M.; Abendroth, F.; Goli, L.; Burrell, M.; Thom, G.; Gurrell, I. Systemic antibody-oligonucleotide delivery to the central nervous system ameliorates mouse models of spinal muscular atrophy. bioRxiv, 2021.
[http://dx.doi.org/10.1101/2021.07.29.454272]
[53]
Bohnert, T.; Gan, L.S. Plasma protein binding: From discovery to development. J. Pharm. Sci., 2013, 102(9), 2953-2994.
[http://dx.doi.org/10.1002/jps.23614] [PMID: 23798314]
[54]
Geary, R.S.; Watanabe, T.A.; Truong, L.; Freier, S.; Lesnik, E.A.; Sioufi, N.B.; Sasmor, H.; Manoharan, M.; Levin, A.A. Pharmacokinetic properties of 2′-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J. Pharmacol. Exp. Ther., 2001, 296(3), 890-897.
[PMID: 11181921]
[55]
Brown, D.A.; Kang, S.H.; Gryaznov, S.M.; DeDionisio, L.; Heidenreich, O.; Sullivan, S.; Xu, X.; Nerenberg, M.I. Effect of phosphorothio-ate modification of oligodeoxynucleotides on specific protein binding. J. Biol. Chem., 1994, 269(43), 26801-26805.
[http://dx.doi.org/10.1016/S0021-9258(18)47090-1] [PMID: 7929417]
[56]
Liang, X.; Sun, H.; Shen, W.; Crooke, S.T. Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages. Nucleic Acids Res., 2015, 43(5), 2927-2945.
[http://dx.doi.org/10.1093/nar/gkv143] [PMID: 25712094]
[57]
Shen, W.; De Hoyos, C.L.; Sun, H.; Vickers, T.A.; Liang, X.; Crooke, S.T. Acute hepatotoxicity of 2′ fluoro-modified 5–10–5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins. Nucleic Acids Res., 2018, 46(5), 2204-2217.
[http://dx.doi.org/10.1093/nar/gky060] [PMID: 29390093]
[58]
Dhuri, K.; Bechtold, C.; Quijano, E.; Pham, H.; Gupta, A.; Vikram, A.; Bahal, R. Antisense oligonucleotides: An emerging area in drug discovery and development. J. Clin. Med., 2020, 9(6), 2004.
[http://dx.doi.org/10.3390/jcm9062004] [PMID: 32604776]
[59]
Amantana, A.; Iversen, P. Pharmacokinetics and biodistribution of phosphorodiamidate morpholino antisense oligomers. Curr. Opin. Pharmacol., 2005, 5(5), 550-555.
[http://dx.doi.org/10.1016/j.coph.2005.07.001] [PMID: 16087398]
[60]
Roberts, T.C.; Langer, R.; Wood, M.J.A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov., 2020, 19(10), 673-694.
[http://dx.doi.org/10.1038/s41573-020-0075-7] [PMID: 32782413]
[61]
Scoles, D.R.; Minikel, E.V.; Pulst, S.M. Antisense oligonucleotides. Neurol. Genet., 2019, 5(2), e323.
[http://dx.doi.org/10.1212/NXG.0000000000000323] [PMID: 31119194]
[62]
Yang, W. Nucleases: Diversity of structure, function and mechanism. Q. Rev. Biophys., 2011, 44(1), 1-93.
[http://dx.doi.org/10.1017/S0033583510000181] [PMID: 20854710]
[63]
U.S. Food and drug administration. FDA Product label. 2016. Available from : https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209531lbl.pdf
[64]
Geary, R.S.; Baker, B.F.; Crooke, S.T. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro(®)): A second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin. Pharmacokinet., 2015, 54(2), 133-146.
[http://dx.doi.org/10.1007/s40262-014-0224-4] [PMID: 25559341]
[65]
Crooke, S.T.; Geary, R.S. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br. J. Clin. Pharmacol., 2013, 76(2), 269-276.
[http://dx.doi.org/10.1111/j.1365-2125.2012.04469.x] [PMID: 23013161]
[66]
Post, N.; Yu, R.; Greenlee, S.; Gaus, H.; Hurh, E.; Matson, J.; Wang, Y. Metabolism and disposition of volanesorsen, a 2′- O -(2 methoxy-ethyl) antisense oligonucleotide, across species. Drug Metab. Dispos., 2019, 47(10), 1164-1173.
[http://dx.doi.org/10.1124/dmd.119.087395] [PMID: 31350288]
[67]
Crooke, R.M.; Graham, M.J.; Martin, M.J.; Lemonidis, K.M.; Wyrzykiewiecz, T.; Cummins, L.L. Metabolism of antisense oligonucleo-tides in rat liver homogenates. J. Pharmacol. Exp. Ther., 2000, 292(1), 140-149.
[PMID: 10604941]
[68]
Geary, R.S.; Leeds, J.M.; Henry, S.P.; Monteith, D.K.; Levin, A.A. Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des., 1997, 12(5), 383-393.
[PMID: 9236854]
[69]
Crooke, S.T. Basic principles of antisense therapeutics. Antisense research and application; Springer, 1998, pp. 1-50.
[http://dx.doi.org/10.1007/978-3-642-58785-6]
[70]
Nicklin, P.; Craig, S.; Phillips, J. Pharmacokinetic properties of phosphorothioates in animals—absorption, distribution, metabolism and elimination. Antisense Research and Application; Springer, 1998, pp. 141-168.
[71]
Cohen, A.S.; Bourque, A.J.; Wang, B.H.; Smisek, D.L.; Belenky, A. A nonradioisotope approach to study the in vivo metabolism of phos-phorothioate oligonucleotides. Antisense Nucleic Acid Drug Dev., 1997, 7(1), 13-22.
[http://dx.doi.org/10.1089/oli.1.1997.7.13] [PMID: 9055034]
[72]
Shemesh, C.S.; Yu, R.Z.; Gaus, H.J.; Greenlee, S.; Post, N.; Schmidt, K.; Migawa, M.T.; Seth, P.P.; Zanardi, T.A.; Prakash, T.P.; Swayze, E.E.; Henry, S.P.; Wang, Y. Elucidation of the biotransformation pathways of a galnac3-conjugated antisense oligonucleotide in rats and monkeys. Mol. Ther. Nucleic Acids, 2016, 5(5), e319.
[http://dx.doi.org/10.1038/mtna.2016.31] [PMID: 27164023]
[73]
Sewell, K.L.; Geary, R.S.; Baker, B.F.; Glover, J.M.; Mant, T.G.K.; Yu, R.Z.; Tami, J.A.; Dorr, F.A. Phase I trial of ISIS 104838, a 2′-methoxyethyl modified antisense oligonucleotide targeting tumor necrosis factor-alpha. J. Pharmacol. Exp. Ther., 2002, 303(3), 1334-1343.
[http://dx.doi.org/10.1124/jpet.102.036749] [PMID: 12438559]
[74]
Geary, R.S.; Yu, R.Z.; Watanabe, T.; Henry, S.P.; Hardee, G.E.; Chappell, A.; Matson, J.; Sasmor, H.; Cummins, L.; Levin, A.A. Pharma-cokinetics of a tumor necrosis factor-α phosphorothioate 2′- O-(2-METHOXYETHYL) modified antisense oligonucleotide: Comparison across species. Drug Metab. Dispos., 2003, 31(11), 1419-1428.
[http://dx.doi.org/10.1124/dmd.31.11.1419] [PMID: 14570775]
[75]
Huang, Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol. Ther. Nucleic Acids, 2017, 6, 116-132.
[http://dx.doi.org/10.1016/j.omtn.2016.12.003] [PMID: 28325278]
[76]
Crooke, S.T.; Baker, B.F.; Xia, S.; Yu, R.Z.; Viney, N.J.; Wang, Y.; Tsimikas, S.; Geary, R.S. Integrated assessment of the clinical perfor-mance of GalNAc 3 -Conjugated 2′- O -methoxyethyl chimeric antisense oligonucleotides: I. Human volunteer experience. Nucleic Acid Ther., 2019, 29(1), 16-32.
[http://dx.doi.org/10.1089/nat.2018.0753] [PMID: 30570431]
[77]
Wang, Y.; Yu, R.Z.; Henry, S.; Geary, R.S. Pharmacokinetics and clinical pharmacology considerations of GalNAc 3 -Conjugated antisense oligonucleotides. Expert Opin. Drug Metab. Toxicol., 2019, 15(6), 475-485.
[http://dx.doi.org/10.1080/17425255.2019.1621838] [PMID: 31144994]
[78]
Bon, C.; Hofer, T.; Bousquet-Mélou, A.; Davies, M.R.; Krippendorff, B.F. Capacity limits of asialoglycoprotein receptor-mediated liver targeting. MAbs, 2017, 9(8), 1360-1369.
[http://dx.doi.org/10.1080/19420862.2017.1373924] [PMID: 28876162]
[79]
Debacker, A.J.; Voutila, J.; Catley, M.; Blakey, D.; Habib, N. Delivery of oligonucleotides to the liver with GalNAc: From research to regis-tered therapeutic drug. Mol. Ther., 2020, 28(8), 1759-1771.
[http://dx.doi.org/10.1016/j.ymthe.2020.06.015] [PMID: 32592692]
[80]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Medical Review (s), Application Number: 209531Orig1s000; , 2017. Available from :[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531orig1s000medr.pdf
[81]
European Medical Agency, Committee for Medicinal Products for Human Use Committee for Medicinal Products for Human Use. As-sessment report, Procedure No. EMEA/H/C/004312/0000; , 2017. Available from :[https://www.ema.europa.eu/en/documents/assessment-report/spinraza-epar-public-assessment-report_en.pdf
[82]
Japan pharmaceuticals and medical devices agency. Review report Spinraza. 2017. Available from : https://www.pmda.go.jp/files/000228334.pdf.
[83]
Chiriboga, C.A.; Swoboda, K.J.; Darras, B.T.; Iannaccone, S.T.; Montes, J.; De Vivo, D.C.; Norris, D.A.; Bennett, C.F.; Bishop, K.M. Re-sults from a phase 1 study of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy. Neurology, 2016, 86(10), 890-897.
[http://dx.doi.org/10.1212/WNL.0000000000002445] [PMID: 26865511]
[84]
Emami, A.; Tepper, J.; Short, B.; Yaksh, T.L.; Bendele, A.M.; Ramani, T.; Cisternas, A.F.; Chang, J.H.; Mellon, R.D. Toxicology evalua-tion of drugs administered via uncommon routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular. Int. J. Toxicol., 2018, 37(1), 4-27.
[http://dx.doi.org/10.1177/1091581817741840] [PMID: 29264927]
[85]
Rigo, F.; Chun, S.J.; Norris, D.A.; Hung, G.; Lee, S.; Matson, J.; Fey, R.A.; Gaus, H.; Hua, Y.; Grundy, J.S.; Krainer, A.R.; Henry, S.P.; Bennett, C.F. Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligo-nucleotide in mice and nonhuman primates. J. Pharmacol. Exp. Ther., 2014, 350(1), 46-55.
[http://dx.doi.org/10.1124/jpet.113.212407] [PMID: 24784568]
[86]
Sullivan, J.M.; Mazur, C.; Wolf, D.A.; Horky, L.; Currier, N.; Fitzsimmons, B.; Hesterman, J.; Pauplis, R.; Haller, S.; Powers, B.; Tayefeh, L.; DeBrosse-Serra, B.; Hoppin, J.; Kordasiewicz, H.; Swayze, E.E.; Verma, A. Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system. J. Transl. Med., 2020, 18(1), 309.
[http://dx.doi.org/10.1186/s12967-020-02461-2] [PMID: 32771027]
[87]
Levin, A.A.; Rosie, Z.Y.; Geary, R.S. Basic principles of the pharmacokinetics of antisense oligonucleotide drugs; Antisense drug technolo-gy, 2nd ed; CRC Press, 2007, pp. 201-234.
[88]
Tillman, L.G.; Geary, R.S.; Hardee, G.E. Oral delivery of antisense oligonucleotides in man. J. Pharm. Sci., 2008, 97(1), 225-236.
[http://dx.doi.org/10.1002/jps.21084] [PMID: 17721945]
[89]
Wang, S.; Sun, H.; Tanowitz, M.; Liang, X.; Crooke, S.T. Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to intracellular release of phosphorothioate-modified antisense oligonucleotides. Nucleic Acids Res., 2017, 45(9), 5309-5322.
[http://dx.doi.org/10.1093/nar/gkx231] [PMID: 28379543]
[90]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Pharmacology Review (s), Application Number: 206488Orig1s000; , 2015. Available from :[https://www.accessdata. fda.gov/drugsatfda_docs/nda/2016/206488Orig1s000PharmR.pdf
[91]
Kim, J.; Basiri, B.; Hassan, C.; Punt, C.; van der Hage, E.; den Besten, C.; Bartlett, M.G. Metabolite profiling of the antisense oligonucleo-tide eluforsen using liquid chromatography-mass spectrometry. Mol. Ther. Nucleic Acids, 2019, 17, 714-725.
[http://dx.doi.org/10.1016/j.omtn.2019.07.006] [PMID: 31422288]
[92]
Crooke, S.T. Antisense drug technology: Principles, strategies, and applications; CRC press, 2007, p. 848.
[http://dx.doi.org/10.1201/9780849387951]
[93]
Yu, R.Z.; Grundy, J.S.; Henry, S.P.; Kim, T.W.; Norris, D.A.; Burkey, J.; Wang, Y.; Vick, A.; Geary, R.S. Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2′-o-(2-methoxyethyl) modi-fications. Mol. Ther. Nucleic Acids, 2015, 4(1), e218.
[http://dx.doi.org/10.1038/mtna.2014.69] [PMID: 25602582]
[94]
Callies, S.; André, V.; Patel, B.; Waters, D.; Francis, P.; Burgess, M.; Lahn, M. Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide. Br. J. Clin. Pharmacol., 2011, 71(3), 416-428.
[http://dx.doi.org/10.1111/j.1365-2125.2010.03836.x] [PMID: 21284701]
[95]
Sophie, C.; Valerie, A.; Andrew-Mark, V.; Jeremy, G.; Bharvin, P.; Leslie, B. 2007.
[96]
Biliouris, K.; Gaitonde, P.; Yin, W.; Norris, D.A.; Wang, Y.; Henry, S.; Fey, R.; Nestorov, I.; Schmidt, S.; Rogge, M.; Lesko, L.J.; Trame, M.N. A semi‐mechanistic population pharmacokinetic model of nusinersen: An antisense oligonucleotide for the treatment of spinal mus-cular atrophy. CPT Pharmacometrics Syst. Pharmacol., 2018, 7(9), 581-592.
[http://dx.doi.org/10.1002/psp4.12323] [PMID: 30043511]
[97]
Yu, R.Z.; Lemonidis, K.M.; Graham, M.J.; Matson, J.E.; Crooke, R.M.; Tribble, D.L.; Wedel, M.K.; Levin, A.A.; Geary, R.S. Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. Biochem. Pharmacol., 2009, 77(5), 910-919.
[http://dx.doi.org/10.1016/j.bcp.2008.11.005] [PMID: 19056355]
[98]
U.S. Food and drug administration, center for drug evaluation andresearch. Clinical pharmacology considerations for the development of oligonucleotide therapeutics. 2022. Available from : https://www.fda.gov/media/159414/download
[99]
Shemesh, C.S.; Yu, R.Z.; Warren, M.S.; Liu, M.; Jahic, M.; Nichols, B.; Post, N.; Lin, S.; Norris, D.A.; Hurh, E.; Huang, J.; Watanabe, T.; Henry, S.P.; Wang, Y. Assessment of the drug interaction potential of unconjugated and GalNAc3-Conjugated 2′-MOE-ASOs. Mol. Ther. Nucleic Acids, 2017, 9, 34-47.
[http://dx.doi.org/10.1016/j.omtn.2017.08.012] [PMID: 29246313]
[100]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Medical Review (s), Application Number: 203568Orig1s000; , 2012. Available from[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203568Orig1s000MedR.pdf
[101]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Non-Clinical Review (s), Application Number: 211172Orig1s000; , 2017. Available from[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211172Orig1s000PharmR.pdf
[102]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Non-Clinical Review (s), Application Number: 211970Orig1s000; , 2018. Available from[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211970Orig1s000PharmR.pdf
[103]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Clinical Pharmacology Review (s), Application Number: 212154Orig1s000; , 2019. Available from[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212154Orig1s000ClinPharmR.pdf
[104]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research Pharmacology Review (s), Application Number: 213026Orig1s000; , 2021. Available from[https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213026Orig1s000PharmR.pdf
[105]
Kazmi, F.; Yerino, P.; McCoy, C.; Parkinson, A.; Buckley, D.B.; Ogilvie, B.W. An assessment of the in vitro inhibition of cytochrome P450 Enzymes, UDP-Glucuronosyltransferases, and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides. Drug Metab. Dispos., 2018, 46(8), 1066-1074.
[http://dx.doi.org/10.1124/dmd.118.081729] [PMID: 29735754]
[106]
Vassiliou, D.; Sardh, E.; Harper, P.; Simon, A.R.; Clausen, V.A.; Najafian, N.; Robbie, G.J.; Agarwal, S. A drug‐drug interaction study evaluating the effect of givosiran, a small interfering ribonucleic acid, on cytochrome p450 activity in the liver. Clin. Pharmacol. Ther., 2021, 110(5), 1250-1260.
[http://dx.doi.org/10.1002/cpt.2419] [PMID: 34510420]
[107]
Humphreys, S.C.; Davis, J.A.; Iqbal, S.; Kamel, A.; Kulmatycki, K.; Lao, Y.; Liu, X.; Rodgers, J.; Snoeys, J.; Vigil, A.; Weng, Y.; Wiethoff, C.M.; Wittwer, M.B. Considerations and recommendations for assessment of plasma protein binding and drug–drug interactions for siR-NA therapeutics. Nucleic Acids Res., 2022, 50(11), 6020-6037.
[http://dx.doi.org/10.1093/nar/gkac456] [PMID: 35687098]
[108]
Tremblay, G.A.; Oldfield, P.R. Bioanalysis of siRNA and oligonucleotide therapeutics in biological fluids and tissues. Bioanalysis, 2009, 1(3), 595-609.
[http://dx.doi.org/10.4155/bio.09.66] [PMID: 21083155]
[109]
Kilanowska, A.; Nuckowski, Ł.; Studzińska, S. Studying in vitro metabolism of the first and second generation of antisense oligonucleo-tides with the use of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Anal. Bioanal. Chem., 2020, 412(27), 7453-7467.
[http://dx.doi.org/10.1007/s00216-020-02878-0] [PMID: 32856108]
[110]
Kotapati, S.; Deshpande, M.; Jashnani, A.; Thakkar, D.; Xu, H.; Dollinger, G. The role of ligand-binding assay and LC–MS in the bioanal-ysis of complex protein and oligonucleotide therapeutics. Bioanalysis, 2021, 13(11), 931-954.
[http://dx.doi.org/10.4155/bio-2021-0009] [PMID: 33998268]
[111]
Li, P.; Dupuis, J.F.; Vrionis, V.; Mekhssian, K.; Magee, T.; Yuan, L. Validation and application of hybridization liquid chromatography-tandem mass spectrometry methods for quantitative bioanalysis of antisense oligonucleotides. Bioanalysis, 2022, 14(9), 589-601.
[http://dx.doi.org/10.4155/bio-2022-0015] [PMID: 35545949]
[112]
Sun, Y.; Nitta, S.; Saito, K.; Hosogai, R.; Nakai, K.; Goda, R.; Kakehi, M.; Murata, K.; Yamaguchi, T.; Okuzono, T.; Yamane, S.; Enoki, Y.; Kawabata, M.; Takahara, K.; Sato, S.; Yoshida, T.; Inoue, T.; Saito, Y. Development of a bioanalytical method for an antisense thera-peutic using high-resolution mass spectrometry. Bioanalysis, 2020, 12(24), 1739-1756.
[http://dx.doi.org/10.4155/bio-2020-0225] [PMID: 33242248]
[113]
Wang, L. Oligonucleotide bioanalysis: Sensitivity versus specificity. Bioanalysis, 2011, 3(12), 1299-1303.
[http://dx.doi.org/10.4155/bio.11.111] [PMID: 21679020]
[114]
Li, P.; Gong, Y.; Kim, J.; Liu, X.; Gilbert, J.; Kerns, H.M.; Groth, R.; Rooney, M. Hybridization liquid chromatography–tandem mass spectrometry: An alternative bioanalytical method for antisense oligonucleotide quantitation in plasma and tissue samples. Anal. Chem., 2020, 92(15), 10548-10559.
[http://dx.doi.org/10.1021/acs.analchem.0c01382] [PMID: 32628461]
[115]
Sutton, J.M.; Kim, J.; El Zahar, N.M.; Bartlett, M.G. Bioanalysis and biotransformation of oligonucleotide therapeutics by liquid chroma-tography-mass spectrometry. Mass Spectrom. Rev., 2021, 40(4), 334-358.
[http://dx.doi.org/10.1002/mas.21641] [PMID: 32588492]
[116]
Guimaraes, G.; Yuan, L.; Li, P. Antisense oligonucleotide in vitro protein binding determination in plasma, brain, and cerebral spinal fluid using hybridization lc-ms/ms. Drug Metab. Dispos., 2022, 50(3), 268-276.
[http://dx.doi.org/10.1124/dmd.121.000751] [PMID: 34921096]
[117]
Humphreys, S.C.; Thayer, M.B.; Lade, J.M.; Wu, B.; Sham, K.; Basiri, B.; Hao, Y.; Huang, X.; Smith, R.; Rock, B.M. Plasma and liver protein binding of n -acetylgalactosamine–conjugated small interfering rna. Drug Metab. Dispos., 2019, 47(10), 1174-1182.
[http://dx.doi.org/10.1124/dmd.119.086967] [PMID: 31097425]
[118]
Toma, C.M.; Imre, S.; Vari, C.E.; Muntean, D.L.; Tero-Vescan, A. Ultrafiltration method for plasma protein binding studies and its limita-tions. Processes (Basel), 2021, 9(2), 382.
[http://dx.doi.org/10.3390/pr9020382]
[119]
Li, J.; Liu, J.; Enders, J.; Arciprete, M.; Tran, C.; Aluri, K.; Guan, L.H.; O’Shea, J.; Bisbe, A.; Charissé, K.; Zlatev, I.; Najarian, D.; Xu, Y. Discovery of a novel deaminated metabolite of a single-stranded oligonucleotide in vivo by mass spectrometry. Bioanalysis, 2019, 11(21), 1955-1965.
[http://dx.doi.org/10.4155/bio-2019-0118] [PMID: 31829055]
[120]
Weidolf, L.; Björkbom, A.; Dahlén, A.; Elebring, M.; Gennemark, P.; Hölttä, M.; Janzén, D.; Li, X.; Andersson, S. Distribution and bio-transformation of therapeutic antisense oligonucleotides and conjugates. Drug Discov. Today, 2021, 26(10), 2244-2258.
[http://dx.doi.org/10.1016/j.drudis.2021.04.002] [PMID: 33862193]
[121]
Coughlin, J.E.; Pandey, R.K.; Padmanabhan, S.; O’Loughlin, K.G.; Marquis, J.; Green, C.E.; Mirsalis, J.C.; Iyer, R.P. Metabolism, pharma-cokinetics, tissue distribution, and stability studies of the prodrug analog of an anti-hepatitis B virus dinucleoside phosphorothioate. Drug Metab. Dispos., 2012, 40(5), 970-981.
[http://dx.doi.org/10.1124/dmd.111.044446] [PMID: 22328581]
[122]
Schmidt, S.; Derendorf, H. Applied Pharmacometrics; Springer, 2014.
[http://dx.doi.org/10.1007/978-1-4939-1304-6]
[123]
Monine, M.; Norris, D.; Wang, Y.; Nestorov, I. A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration. J. Pharmacokinet. Pharmacodyn., 2021, 48(5), 639-654.
[http://dx.doi.org/10.1007/s10928-021-09761-0] [PMID: 33991294]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy