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Special ReportOpen Accesscc iconby iconnc iconnd icon

Research and development of oligonucleotide therapeutics in Japan for rare diseases

    Junetsu Igarashi

    *Author for correspondence:

    E-mail Address: igarashj@kyudai.jp

    Kurume Research Park Co., Ltd., 1-1 Hyakunenkoen, Kurume City, Fukuoka, 839-0864, Japan

    Kyushu University, Incubation Center for Advanced Medical Science, 3-1-1 Maidashi, Higashi-Ku, Fukuoka City, Fukuoka, 812-8582, Japan

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    ,
    Yasuharu Niwa

    Kyushu University, Incubation Center for Advanced Medical Science, 3-1-1 Maidashi, Higashi-Ku, Fukuoka City, Fukuoka, 812-8582, Japan

    Fujita Health University, International Center for Cell & Gene Therapy, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake City, Aichi, 470-1192, Japan

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    &
    Daisuke Sugiyama

    Kyushu University, Incubation Center for Advanced Medical Science, 3-1-1 Maidashi, Higashi-Ku, Fukuoka City, Fukuoka, 812-8582, Japan

    National Hospital Organization Hiroshima-Nishi Medical Center, 4-1-1, Kuba-Cho, Otake City, Hiroshima, 739-0696, Japan

    Hiroshima University, Translational Research Center, 1-2-3 Kasumi, Minami-Ku, Hiroshima City, Hiroshima, 734-8551, Japan

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    Published Online:28 Feb 2022https://doi.org/10.2217/frd-2021-0008

    Abstract

    Inherited gene mutations, insertions, deletions of single genes cause most of the rare diseases. Oligonucleotide therapeutics represent one of the most flexible platforms for developing drugs for rare diseases. Presently, 15 oligonucleotide therapeutics have been approved in the United States of America (USA) to treat various rare diseases and 4 oligonucleotide therapeutics (eteplirsen, golodirsen, viltolarsen and casimersen) are used to treat Duchenne muscular dystrophy. The progress of oligonucleotide therapeutics in Japan has emerged from several decades of basic research. In March 2020, viltolarsen, developed by Japanese companies, was approved as a treatment for Duchenne muscular dystrophy. This article discusses the research and development of oligonucleotide therapeutics for rare diseases from the viewpoint of the proprietary technologies in Japanese pharmaceutical and bio-venture companies.

    Plain language summary

    Recently, oligonucleotide therapeutics have received awareness following small molecule and antibody drugs. The research related to oligonucleotide therapeutics in Japan is based on the results of basic research accumulated over several decades. For example, viltolarsen (NS-065/NCNP-01) from Nippon Shinyaku was approved for Duchenne muscular dystrophy in Japan and USA in 2020. Here, we report the development of oligonucleotide therapeutics and the role of Japan.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Melnikova I. Rare diseases and orphan drugs. Nat. Rev. Drug Discov. 11(4), 267–268 (2012). • Reports that with seven separate orphan drug approvals, imatinib (Gleevec; Novartis) is one of the most commercially successful drugs for treating rare diseases.
      Google Scholar
    • 2. Pariser AR, Gahl WA. Important role of translational science in rare disease innovation, discovery, and drug development. J. Gen. Intern. Med. 29(Suppl. 3), S804–S807 (2014). •• Reports that rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science.
      Google Scholar
    • 3. Dunoyer M. Accelerating access to treatments for rare diseases. Nat Rev Drug Discov 10(7), 475–476 (2011). • Reports that changes in regulatory policy and legislative incentives to promote the development of drugs for rare diseases.
      Google Scholar
    • 4. Tambuyzer E, Vandendriessche B, Austin CP et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov 19(2), 93–111 (2020). • Reports that most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies.
      CASGoogle Scholar
    • 5. Lefebvre S, Burglen L, Reboullet S et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1), 155–165 (1995).
      Google Scholar
    • 6. Yin W, Rogge M. Targeting RNA: A Transformative Therapeutic Strategy. Clin Transl Sci 12(2), 98–112 (2019). •• Reports that oligonucleotide therapeutics is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets.
      Google Scholar
    • 7. Yamamoto T, Nakatani M, Narukawa K, Obika S. Antisense drug discovery and development. Future Med Chem 3(3), 339–365 (2011).
      Google Scholar
    • 8. Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13(8), 622–638 (2014).
      Google Scholar
    • 9. Akimoto S, Suzuki JI, Aoyama N et al. A novel bioabsorbable sheet that delivers NF-kappaB decoy oligonucleotide restrains abdominal aortic aneurysm development in rats. Int Heart J 59(5), 1134–1141 (2018).
      Google Scholar
    • 10. Stein CA, Castanotto D. FDA-approved oligonucleotide therapies in 2017. Mol Ther 25(5), 1069–1075 (2017).
      Google Scholar
    • 11. Vollmer J, Krieg AM. Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Deliv Rev 61(3), 195–204 (2009).
      Google Scholar
    • 12. Sullenger BA, Nair S. From the RNA world to the clinic. Science 352(6292), 1417–1420 (2016).
      Google Scholar
    • 13. Schein A, Zucchelli S, Kauppinen S, Gustincich S, Carninci P. Identification of antisense long noncoding RNAs that function as SINEUPs in human cells. Sci Rep 6, 33605 (2016).
      Google Scholar
    • 14. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171(4356), 737–738 (1953).
      Google Scholar
    • 15. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669), 806–811 (1998).
      Google Scholar
    • 16. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411(6836), 494–498 (2001).
      Google Scholar
    • 17. Abdulhay NJ, Fiorini C, Verboon JM et al. Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation. J. Exp. Med. 216(5), 1050–1060 (2019).
      Google Scholar
    • 18. Aartsma-Rus A. FDA Approval of Nusinersen for Spinal Muscular Atrophy Makes 2016 the Year of Splice Modulating Oligonucleotides. Nucleic Acid Ther 27(2), 67–69 (2017).
      Google Scholar
    • 19. Keam SJ. Inotersen: First Global Approval. Drugs 78(13), 1371–1376 (2018).
      Google Scholar
    • 20. Adams D, Gonzalez-Duarte A, O'riordan WD et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N. Engl. J. Med. 379(1), 11–21 (2018).
      Google Scholar
    • 21. Witztum JL, Gaudet D, Freedman SD et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N. Engl. J. Med. 381(6), 531–542 (2019).
      Google Scholar
    • 22. Scott LJ. Givosiran: First Approval. Drugs 80(3), 335–339 (2020).
      MedlineGoogle Scholar
    • 23. Heo YA. Golodirsen: First Approval. Drugs 80(3), 329–333 (2020).
      Google Scholar
    • 24. Komaki H, Nagata T, Saito T et al. Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci Transl Med 10(437), (2018).
      Google Scholar
    • 25. Garrelfs SF, Frishberg Y, Hulton SA et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N. Engl. J. Med. 384(13), 1216–1226 (2021).
      Medline CASGoogle Scholar
    • 26. Lamb YN. Inclisiran: First Approval. Drugs 81(3), 389–395 (2021).
      Medline CASGoogle Scholar
    • 27. Shirley M. Casimersen: First Approval. Drugs 81(7), 875–879 (2021).
      Google Scholar
    • 28. Shen X, Corey DR. Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 46(4), 1584–1600 (2018).
      Google Scholar
    • 29. Bennett CF, Baker BF, Pham N, Swayze E, Geary RS. Pharmacology of Antisense Drugs. Annu. Rev. Pharmacol. Toxicol. 57, 81–105 (2017).
      Google Scholar
    • 30. Satoshi Obika DN, Yoshiyuki Hari, Ken Ichiro Morio, Yasuko IN, Toshimasa Ishida, Takeshi Imanishi. Synthesis of 2′-O,4′-C-Methyleneuridine and -cytidine. Novel Bicyclic Nucleosides Having a Fixed C3′-endo Sugar Puckering. Tetrahedron Lett 38, 8735–8738 (1997).
      Google Scholar
    • 31. Mendell JR, Goemans N, Lowes LP et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann. Neurol. 79(2), 257–271 (2016).
      Google Scholar
    • 32. Prakash TP. An overview of sugar-modified oligonucleotides for antisense therapeutics. Chem Biodivers 8(9), 1616–1641 (2011). • Reports that among the multitude of chemical modifications that have been described over the past two decades, oligonucleotide analogs that are modified at the 2′-position of the furanose sugar have been especially useful for improving the drug-like properties of antisense oligonucleotides.
      Google Scholar
    • 33. Obika S, Nanbu D, Hari Y et al. Stability and structural features of the duplexes containing nucleoside analogues with a fixed N-type conformation, 2′-O,4′-C-methyleneribonucleosides. Tetrahedron Lett 39(30), 5401–5404 (1998).
      Google Scholar
    • 34. Habuchi T, Yamaguchi T, Aoyama H, Horiba M, Ito KR, Obika S. Hybridization and mismatch discrimination abilities of 2′,4′-bridged nucleic acids bearing 2-thiothymine or 2-selenothymine nucleobase. J Org Chem 84(3), 1430–1439 (2019).
      Google Scholar
    • 35. Morita K, Koizumi M. Synthesis of ENA Nucleotides and ENA Oligonucleotides. Curr Protoc Nucleic Acid Chem 72(1), 4 79 71–74 79 21 (2018).
      Google Scholar
    • 36. Shen W, De Hoyos CL, Migawa MT et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat Biotechnol 37(6), 640–650 (2019).
      Google Scholar
    • 37. Lee T, Awano H, Yagi M et al. 2′-O-Methyl RNA/ethylene-bridged nucleic acid chimera antisense oligonucleotides to induce dystrophin exon 45 skipping. Genes (Basel) 8(2), 67 (2017).
      Google Scholar
    • 38. Uehara T, Choong CJ, Nakamori M et al. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting alpha-synuclein as a novel therapy for Parkinson's disease. Sci Rep 9(1), 7567 (2019).
      Google Scholar
    • 39. Shrestha AR, Kotobuki Y, Hari Y, Obika S. Guanidine bridged nucleic acid (GuNA): an effect of a cationic bridged nucleic acid on DNA binding affinity. Chem Commun (Camb) 50(5), 575–577 (2014).
      Google Scholar
    • 40. Horiba M, Yamaguchi T, Obika S. Synthesis of scpBNA-(m)C, -A, and -G monomers and evaluation of the binding affinities of scpbna-modified oligonucleotides toward complementary ssRNA and ssDNA. J Org Chem 81(22), 11000–11008 (2016).
      Google Scholar
    • 41. Komine H, Mori S, Morihiro K et al. Synthesis and evaluation of artificial nucleic acid bearing an oxanorbornane scaffold. Molecules 25(7), 1732 (2020).
      Google Scholar
    • 42. Hamasaki T, Matsumoto T, Sakamoto N et al. Synthesis of 18O-labeled RNA for application to kinetic studies and imaging. Nucleic Acids Res. 41(12), e126 (2013).
      Google Scholar
    • 43. Smith M. The role of chemical synthesis in establishing gene function by in vitro mutagenesis. Proc. Robert A. Welch Found. Conf. Chem. Res. 29, 439–455 (1985).
      Google Scholar
    • 44. Takahashi D, Inomata T, Fukui T. AJIPHASE(R): a highly efficient synthetic method for one-pot peptide elongation in the solution phase by an Fmoc strategy. Angew Chem Int Ed Engl 56(27), 7803–7807 (2017).
      Google Scholar
    • 45. Watanabe N, Nagata T, Satou Y et al. NS-065/NCNP-01: an antisense oligonucleotide for potential treatment of exon 53 skipping in Duchenne muscular dystrophy. Mol Ther Nucleic Acids 13, 442–449 (2018).
      Google Scholar
    • 46. Suzuki K, Yokoyama J, Kawauchi Y et al. Phase 1 clinical study of sirna targeting carbohydrate sulphotransferase 15 in Crohn's disease patients with active mucosal lesions. J Crohns Colitis 11(2), 221–228 (2017).
      Google Scholar
    • 47. Miyake T, Miyake T, Sakaguchi M, Nankai H, Nakazawa T, Morishita R. Prevention of asthma exacerbation in a mouse model by simultaneous inhibition of NF-kappaB and STAT6 activation using a chimeric decoy strategy. Mol Ther Nucleic Acids 10, 159–169 (2018).
      Google Scholar
    • 48. Miyanishi K, Takayama T, Ohi M et al. Glutathione S-transferase-pi overexpression is closely associated with K-ras mutation during human colon carcinogenesis. Gastroenterology 121(4), 865–874 (2001).
      Google Scholar
    • 49. Ishiwatari H, Sato Y, Murase K et al. Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes. Gut 62(9), 1328–1339 (2013).
      Google Scholar
    • 50. Molitoris BA, Dagher PC, Sandoval RM et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J. Am. Soc. Nephrol. 20(8), 1754–1764 (2009).
      Google Scholar
    • 51. Fujiwara T, Katsuda T, Hagiwara K et al. Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells. Stem Cells 32(4), 959–973 (2014).
      Google Scholar
    • 52. Honma K, Iwao-Koizumi K, Takeshita F et al. RPN2 gene confers docetaxel resistance in breast cancer. Nat. Med. 14(9), 939–948 (2008).
      Google Scholar
    • 53. Futami K, Kimoto M, Lim YWS, Hirao I. Genetic alphabet expansion provides versatile specificities and activities of unnatural-base DNA aptamers targeting cancer cells. Mol Ther Nucleic Acids 14, 158–170 (2019).
      Google Scholar
    • 54. Matsunaga K, Kimoto M, Hanson C, Sanford M, Young HA, Hirao I. Architecture of high-affinity unnatural-base DNA aptamers toward pharmaceutical applications. Sci Rep 5, 18478 (2015).
      Google Scholar