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WO2021251526A1 - Nouveaux analogues de miarn et leurs utilisations - Google Patents

Nouveaux analogues de miarn et leurs utilisations Download PDF

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Publication number
WO2021251526A1
WO2021251526A1 PCT/KR2020/007578 KR2020007578W WO2021251526A1 WO 2021251526 A1 WO2021251526 A1 WO 2021251526A1 KR 2020007578 W KR2020007578 W KR 2020007578W WO 2021251526 A1 WO2021251526 A1 WO 2021251526A1
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Prior art keywords
cancer
hsa
mir
seq
analog
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PCT/KR2020/007578
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English (en)
Korean (ko)
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최혜인
박병순
최은욱
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주식회사 프로스테믹스
주식회사 인터셀라
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Priority to PCT/KR2020/007578 priority Critical patent/WO2021251526A1/fr
Publication of WO2021251526A1 publication Critical patent/WO2021251526A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing

Definitions

  • the present invention relates to novel miRNA analogs and various uses thereof.
  • miRNA is a small non-coding RNA composed of 18-25 nucleotides (nucleotide, nt), which binds to the 3'-untranslated region (UTR) of a target gene and regulates gene expression (Bartel DP, et al. , Cell 116: 281-297, 2004; Lewis BP, et al., Cell 120: 15-20, 2005) are processed from introns, exons or intergenic regions (Rodriguez A, et al., Genome Res 14: 1902-1910, 2004).
  • miRNAs are transcribed by RNA polymerase into nascent miRNA (pri-miRNA) molecules containing thousands of nucleotides.
  • pri-miRNA is microprocessor [DroshaRNase endonuclease and DiGeorge syndrome region gene 8 protein (DGCR8)) to form an approximately 70 nt stem ring intermediate known as a miRNA precursor. ] (Lee Y, et al., EMBO J21: 4663-4670, 2000; Zeng Y, et al., Proc Natl Acad Sci US A100: 9779-9784, 2003). Then, the pre-miRNA is transported from the nucleus to the cytoplasm via exoportin-5 (Exportin-5, EXP5) and the cofactor Ran-GTP, where the pre-miRNA is 18-25 by the RNase endonuclease Dicer.
  • exoportin-5 Exportin-5, EXP5
  • Ran-GTP cofactor Ran-GTP
  • RNA-induced silencing complex RISC
  • Cancer is one of the most common causes of death worldwide. About 10 million new cases occur each year, accounting for about 12% of all deaths, making it the third leading cause of death.
  • breast cancer is the most common malignant tumor that causes more than 40,000 deaths annually in women, and early diagnosis is very important. This has not improved.
  • Chemotherapy which is a representative anti-cancer therapy, is currently used as the most effective treatment for cancer, either alone or in combination with other therapies such as radiotherapy.
  • the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that it can act not only on cancer cells but also normal cells when the drug is used.
  • cancer stem cells are cancer cells with unlimited regenerative capacity, and the hypothesis that tumors originate from stem cells was hypothesized in the late 1990s to immunosuppress a group of cells that could become cancer stem cells in acute myeloid leukemia. It was confirmed when it was announced that human leukemia could be reproduced in mice by transplantation into mice, and later, by proving cancer stem cells in breast cancer, he became convinced of the existence of stem cells in solid carcinoma.
  • the diverse heterogeneity of malignant tumors is consistent with the diverse differentiation characteristics of stem cells, and the drug resistance of cancer cells, which is constantly expressed despite many targeted therapies, is consistent with the basic characteristics of stem cells. and cancer stem cells can become a new target therapeutic field.
  • Another object of the present invention is to provide various uses using the above oligonucleotides.
  • an oligonucleotide that is an analog of hsa-miR-503-3p, hsa-miR-328-3p, and hsa-miR-6514-5p.
  • the oligonucleotide has 60% or more and less than 100%, 70% or more and less than 100%, 80% homology to the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p represented by SEQ ID NO: 1 It may consist of a nucleotide sequence of 100% or more, or 90% or more and less than 100%.
  • the oligonucleotide includes the seed sequence (ggguauu) of the hsa-miR-503-3p represented by SEQ ID NO: 4, and hsa-miR-503-3p represented by SEQ ID NO: 1
  • the nucleotide sequence (gggguauuguuuccgcugccagg) and homology to 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more and less than 100% may consist of a nucleotide sequence.
  • the oligonucleotide comprises the seed sequence (ggguauu) of the hsa-miR-503-3p represented by SEQ ID NO: 4 as the 2nd to 8th sequences from the 5'-end, 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more 100 It may be composed of a base sequence that is less than %.
  • the oligonucleotide has 60% or more and less than 100%, 70% or more and less than 100%, 80 % or more and less than 100%, or 90% or more and less than 100% may consist of a nucleotide sequence.
  • the oligonucleotide includes the seed sequence (uggcccu) of the hsa-miR-328-3p represented by SEQ ID NO: 5, and hsa-miR-328- represented by SEQ ID NO: 2 It may consist of a nucleotide sequence having 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more and less than 100% of the nucleotide sequence of 3p (cuggcccuucugcccuuccgu).
  • the oligonucleotide comprises the seed sequence (uggcccu) of the hsa-miR-328-3p represented by SEQ ID NO: 5 as the 2nd to 8th sequences from the 5'-end, 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more 100 It may be composed of a base sequence that is less than %.
  • the oligonucleotide has 60% or more and less than 100%, 70% or more and less than 100%, 80 % or more and less than 100%, or 90% or more and less than 100% may consist of a nucleotide sequence.
  • the oligonucleotide includes the seed sequence (auggagu) of the hsa-miR-6514-5p represented by SEQ ID NO: 6, and hsa-miR-6514- represented by SEQ ID NO: 3 It may consist of a nucleotide sequence having 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more and less than 100% of the nucleotide sequence of 5p (uauggaguggacuuucagcuggc).
  • the oligonucleotide includes the seed sequence (auggagu) of the hsa-miR-6514-5p represented by SEQ ID NO: 6 as the 2nd to 8th sequences from the 5'-end,
  • the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p represented by SEQ ID NO: 3 is 60% or more and less than 100%, 70% or more and less than 100%, 80% or more and less than 100%, or 90% or more 100% It may consist of less than a base sequence.
  • the base of at least one nucleic acid among the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p represented by SEQ ID NO: 1 is adenine, guanine, uracil (uracil) and cytosine (cytosine) may be substituted with another type.
  • the base of at least one nucleic acid among the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p represented by SEQ ID NO: 2 is adenine, guanine, uracil (uracil) and cytosine (cytosine) may be substituted with another type.
  • the base of at least one nucleic acid among the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p represented by SEQ ID NO: 3 is adenine, guanine, uracil (uracil) and cytosine (cytosine) may be substituted with another type of base.
  • a nucleic acid substituted with a different type refers to, for example, a case in which the base of the nucleic acid is adenine, and the base is substituted with guanine, uracil or cytosine instead of adenine.
  • the base of the nucleic acid when the base of the nucleic acid is guanine, it means that the base is not guanine, but is substituted with adenine, uracil or cytosine, and as another example, when the base of the nucleic acid is uracil, This means that the base is substituted with adenine, guanine or cytosine instead of uracil, and as another example, when the base of the nucleic acid is cytosine, it means the case where the base is substituted with adenine, guanine, or uracil.
  • the base (guanine) of the first nucleic acid at the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the second nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the third nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p represented by SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the fourth nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the 5th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p represented by SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (adenine) of the 6th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is guanine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the 7th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (uracil) of the 8th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (guanine) of the ninth nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the 10th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (uracil) of the 11th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (uracil) of the 12th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (cytosine) of the 13th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or uracil.
  • the base (cytosine) of the 14th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or uracil.
  • the base (guanine) of the 15th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 16th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or uracil.
  • the base (uracil) of the 17th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or cytosine.
  • the base (guanine) of the 18th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 19th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or uracil.
  • the base (cytosine) of the 20th nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , may be substituted with guanine or uracil.
  • the base (adenine) of the 21st nucleic acid at the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is guanine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 22nd nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 23rd nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p shown in SEQ ID NO: 1 is adenine , uracil (uracil) or may be substituted with cytosine (cytosine).
  • the oligonucleotide is the 9th, 13th, 15th to 21st nucleic acid from the 5'-end of the nucleotide sequence (gggguauuguuuccgcugccagg) of hsa-miR-503-3p represented by SEQ ID NO: 1. At least one of the bases of the nucleic acid may be substituted with a base of another type among adenine, guanine, uracil, and cytosine.
  • the base (cytosine) of the first nucleic acid at the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (uracil) of the second nucleic acid at the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (guanine) of the third nucleic acid at the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p represented by SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the fourth nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 5th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (cytosine) of the 6th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (cytosine) of the 7th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (uracil) of the 8th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (cytosine) of the ninth nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (uracil) of the 10th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (cytosine) of the 11th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (uracil) of the 12th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (guanine) of the 13th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 14th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (cytosine) of the 15th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (cytosine) of the 16th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (uracil) of the 17th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p represented by SEQ ID NO: 2 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (uracil) of the 18th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine
  • guanine or cytosine may be substituted.
  • the base (cytosine) of the 19th nucleic acid from the 5'-end of the nucleotide sequence (cuggccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (cytosine) of the 20th nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or guanine (guanine) may be substituted.
  • the base (guanine) of the 21st nucleic acid at the 5'-end of the nucleotide sequence (cuggcccucucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine (adenine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the 22nd nucleic acid from the 5'-end of the nucleotide sequence (cuggcccuucugcccuuccgu) of hsa-miR-328-3p shown in SEQ ID NO: 2 is adenine
  • guanine or cytosine may be substituted.
  • the base (uracil) of the first nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine
  • guanine or cytosine may be substituted.
  • the base (adenine) of the second nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is guanine (guanine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the third nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine (adenine) ), guanine or cytosine may be substituted.
  • the base (guanine) of the fourth nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 5th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (adenine) of the 6th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p represented by SEQ ID NO: 3 is guanine (guanine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 7th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (uracil) of the 8th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or cytosine may be substituted.
  • the base (guanine) of the ninth nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 10th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (adenine) of the 11th nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is guanine (guanine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 12th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine
  • guanine or uracil may be substituted.
  • the base (uracil) of the 13th nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or cytosine may be substituted.
  • the base (uracil) of the 14th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or cytosine may be substituted.
  • the base (uracil) of the 15th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or cytosine may be substituted.
  • the base (cytosine) of the 16th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or uracil may be substituted.
  • the base (adenine) of the 17th nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is guanine (guanine) ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 18th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (cytosine) of the 19th nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or uracil may be substituted.
  • the base (uracil) of the 20th nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or cytosine may be substituted.
  • the base (guanine) of the 21st nucleic acid at the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the base (guanine) of the 22nd nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), uracil (uracil) or may be substituted with cytosine (cytosine).
  • the nucleotide (cytosine) of the 23rd nucleic acid from the 5'-end of the nucleotide sequence (uauggaguggacuuucagcuggc) of hsa-miR-6514-5p shown in SEQ ID NO: 3 is adenine ), guanine or uracil may be substituted.
  • the oligonucleotide is an analog of hsa-miR-503-3p, and relates to an oligonucleotide comprising a nucleotide sequence represented by the following formula (1).
  • N 1 to N 9 may be each independently selected from the group consisting of adenine, guanine, uracil and cytosine.
  • N 1 is guanine
  • N 2 is cytosine
  • N 3 is guanine
  • N 4 is cytosine
  • N 5 is uracil
  • N 6 is guanine
  • N 7 is cytosine
  • N 8 is cytosine and N 9 is adenine, except for the case.
  • N 1 may be cytosine.
  • N 2 may be guanine.
  • N 3 may be cytosine.
  • N 4 may be guanine.
  • N 5 may be adenine.
  • N 6 may be cytosine.
  • N 7 may be guanine.
  • N 8 may be guanine.
  • N 9 may be uracil.
  • the oligonucleotide is an analog of hsa-miR-503-3p, and may be represented by any one nucleotide sequence of SEQ ID NOs: 7 to 37, but is not limited thereto.
  • the oligonucleotide is an analog of hsa-miR-328-3p, and may be represented by the nucleotide sequence of any one of SEQ ID NOs: 38 to 59, but is not limited thereto.
  • the oligonucleotide is an analog of hsa-miR-6514-5p, and may be represented by any one of nucleotide sequences of SEQ ID NOs: 60 to 82, but is not limited thereto.
  • the oligonucleotides in the present invention may contain naturally occurring or modified, non-naturally occurring bases, and may contain modified sugars, phosphates and/or termini.
  • phosphate modifications include, but are not limited to, methyl phosphonates, phosphorothioates, phosphoramidates (crosslinked or non-crosslinked), phosphotriesters and phosphorodithioates. not, and may be used in any combination.
  • the RNA oligonucleotide has phosphorothioate linkages alone, phosphodiester linkages alone, or a combination of phosphodiester and phosphorothioate linkages.
  • sugar modifications known in the art such as 2'-alkoxy-RNA analogs, 2'-amino-RNA analogs, 2'-fluoro-DNA, and 2'-alkoxy- or amino-RNA/DNA chimeras and herein Others described may also be prepared and combined with any phosphate modification.
  • base modifications are to C-5 and/or C-6 of cytosine (eg, 5-bromocytosine, 5-chlorocytosine, 5-fluorocytosine, 5-iodocytosine) of the oligonucleotide.
  • an electron-withdrawing moiety and C-5 and/or of uracil eg, 5-bromouracil, 5-chlorouracil, 5-fluorouracil, 5-iodouracil
  • an oligonucleotide of the invention including but not limited to the addition of an electron-withdrawing moiety to C-6.
  • the use of base modifications in the palindromic sequence of the oligonucleotide should not interfere with the self-complementarity of the bases involved for Watson-Crick base pairing. However, outside the palindromic sequence, modified bases can be used without this limitation.
  • 2'-O-methyl-uridine and 2'-O-methyl-cytidine can be used outside the palindromic sequence, whereas 5-bromo-2'-deoxycytidine can be used outside the palindromic sequence. It can be used both inside and outside a grammar sequence.
  • Other modified nucleotides that can be used both inside and outside the palindromic sequence include 7-deaza-8-aza-dG, 2-amino-dA, and 2-thio-dT.
  • the oligonucleotide may include a phosphate-modified oligonucleotide, a part of which is known to stabilize the oligonucleotide. Accordingly, some embodiments of the invention include stabilized oligonucleotides.
  • the synthesis of oligonucleotides containing modified phosphate linkages or non-phosphate linkages is also known in the art (see, e.g., Matteucci "Oligonucleotide Analogs: an Overview" in Oligonucleotides as Therapeutic Agents, (DJ Chadwick and G. Cardew, ed.) John Wiley and Sons, New York, NY, 1997).
  • Phosphorus derivatives that may be attached to a sugar or sugar analog moiety in an oligonucleotide include monophosphate, diphosphate, triphosphate, alkylphosphonate, phosphorothioate, phosphorodithioate, phospho formamidate and the like.
  • phosphorothioate oligonucleotides is similar to that described above for naturally occurring oligonucleotides, except that the oxidation step is replaced by a sulfiding step (Zon "Oligonucleoside Phosphorothioates" in Protocols for Oligonucleotides and Analogs, Synthesis and Properties (Agrawal, ed.) Humana Press, pp. 165-190, 1993).
  • the oligonucleotide may include one or more ribonucleotides (either alone or containing ribose as the main sugar component), deoxyribonucleotides (containing deoxyribose as the main sugar component), modified sugars or sugar analogs.
  • the sugar moiety can be a pentose, deoxypentose, hexose, deoxyhexose, glucose, arabinose, xylose, lyxose, and sugar analog cyclopentyl group.
  • Sugars may exist in either pyranosyl or furanosyl forms.
  • the sugar moiety is preferably a furanoside of ribose, deoxyribose, arabinose or 2'-O-alkyl (eg methyl, ethyl)ribose, and the sugar is each heterocyclic It can be attached in an anomeric configuration to a base.
  • Sugar modifications include 2'-alkoxy (eg, methoxy, ethoxy)-RNA analogs, 2'-amino-RNA analogs, 2'-fluoro-RNA, 2'-fluoro-DNA, and 2'-alkoxy- or amino-RNA/DNA chimeras.
  • heterocyclic bases, or nucleic acid bases incorporated into the oligonucleotides include naturally occurring major purine and pyrimidine bases (i.e., uracil, thymine, cytosine, adenine and guanine as mentioned above) as well as those of the major bases. It can be naturally occurring and synthetically modified. Accordingly, the oligonucleotide of the present invention may comprise one or more of inosine, 2'-deoxyuridine and 2-amino-2'-deoxyadenosine.
  • the oligonucleotides of the invention can be modified using a variety of strategies known in the art to produce a variety of effects, including, for example, improved potency and stability in vitro and in vivo.
  • artificial nucleic acids such as 2'-0-methyl-substituted RNA; 2'-fluoro-2'-deoxy RNA, peptide nucleic acid (PNA); morpholino; locked nucleic acid (LNA); unlocked nucleic acids (UNA); cross-linked nucleic acids (BNA); glycol nucleic acids (GNA); and threose nucleic acid (TNA);
  • analog nucleobases confer different base pairing and base stacking properties, among other things. Examples thereof include universal bases capable of pairing with four canon bases. Examples of phosphate-sugar backbone analogs include PNA. Morpholino-based oligomeric compounds are described in Braasch et al., Biochemistry, 41(14):4503-4510 (2002) and US Pat. Nos. 5,539,082, 5,714,331, 5,719,262 and 5,034,506.
  • the oligonucleotide may be modified by substitution with a chemical functional group at the terminal end. Substitutions may be made at the 3' or 5' end of the oligonucleotide, preferably, but not always, at the 3' end of both the sense and antisense strands of the monomer.
  • Chemical functional groups are, for example, sulfhydryl groups (-SH), carboxyl groups (-COOH), amine groups (-NH2), hydroxy groups (-OH), formyl groups (-CHO), carbonyl groups ( -CO-), an ether group (-O-), an ester group (-COO-), a nitro group (-NO2), an azide group (-N3) or a sulfonic acid group (-SO3H).
  • an expression vector comprising the oligonucleotide provided by the present invention; or to a host cell transformed from the expression vector.
  • the expression vector of the present invention encodes the oligonucleotide of the present invention, preferably in an expressible form.
  • the term "in an expressible form” means that the vector expresses the molecule when introduced into a host cell.
  • the expression vector includes regulatory elements necessary for expression of the oligonucleotide.
  • the expression vector of the present invention can be used for production of the oligonucleotide of the present invention, or can be directly used as an active ingredient for cancer treatment, skin improvement or wound treatment.
  • the expression vector of the present invention can be used in a method of cloning a CX sequence into an expression vector in which the regulatory sequence is functionally linked to the CX sequence, for example, in a method that allows expression of both strands (by transcription of a DNA molecule). by (Lee NS et al., Nat Biotechnol 2002 May, 20(5):500-5).
  • an RNA molecule that is the antisense strand of the oligonucleotide is transcribed by a first promoter (eg, a promoter sequence adjacent to the 3' end of the cloned DNA), and an RNA molecule that is the sense strand is transcribed by a second promoter ( eg, a promoter sequence flanking the 5' end of the cloned DNA).
  • a first promoter eg, a promoter sequence adjacent to the 3' end of the cloned DNA
  • a second promoter eg, a promoter sequence flanking the 5' end of the cloned DNA
  • the sense strand and the anti-sense strand hybridize in vivo and generate an oligonucleotide molecular construct that silencing the corresponding gene.
  • the cloned sequence may encode a construct having a secondary structure (eg a hairpin).
  • the expression vector of the present invention can be used to stably insert into the genome of a target cell (for a description of a homologous recombination cassette vector, see Thomas KR & Capecchi MR, Cell 1987,51:503-12). See, eg, Wolff et al., Science 1990,247:1465-8, US Pat. No. 5,580,859; 5,589,466; 5,804,566; 5,739,118; 5,736,524; 5,679,647; and WO98/04720.
  • DNA-based delivery technologies include “naked DNA”, facilitative (bupivicaine, polymer, peptide-mediated) delivery, cationic lipid complexes and particle- mediated) [”gene gun”] or pressure-mediated delivery (see, eg, US Pat. No. 5,922,687).
  • the expression vector is preferably a non-viral vector or a viral vector
  • the non-viral vector is preferably a plasmid DNA
  • the viral vector is a lentivirus, a retrovirus, Adenovirus (adenovirus), herpes virus (herpes virus) and avipox virus (avipox virus) vectors and the like may be used, but is not limited thereto.
  • the expression vector preferably further includes a selection marker to facilitate selection of transformed cells.
  • a selection marker to facilitate selection of transformed cells.
  • Markers that confer selectable phenotypes such as, for example, drug resistance, auxotrophy, resistance to cytotoxic agents or expression of surface proteins, such as green fluorescent protein, puromycin, neomycin, hygromycin, Histidinol dehydrogenase (hisD) and guanine phosphoribosyltransferase (Gpt) can be exemplified.
  • the host cell is preferably a mammalian somatic cell, including a human, and more preferably a cell of a tissue site targeted for human treatment, or a cancer cell or cancer stem cell of that site, but is not limited thereto.
  • G-fectin, Mirus TrasIT-TKO lipid affinity reagent, lipofectin, lipofectamine, cellfectin (cellfectin), cationic phospholipid nanoparticles It may be introduced into cells together with a delivery reagent including a cationic polymer, cationic micelles, cationic emulsion or liposome, or may be conjugated to a biocompatible polymer such as polyethylene glycol to increase intracellular absorption, but is not limited thereto.
  • compositions for preventing, improving or treating cancer comprising the oligonucleotide, expression vector or transformed host cell provided in the present invention as an active ingredient, a composition for inhibiting growth of cancer stem cells to provide.
  • composition for preventing, improving or treating cancer metastasis comprising the oligonucleotide, expression vector or transformed host cell provided in the present invention as an active ingredient.
  • the composition for preventing, improving or treating cancer can be used for various purposes, such as a pharmaceutical composition or a food composition. .
  • the step of administering an effective amount of the oligonucleotide, expression vector or transformed host cell provided by the present invention to a subject in need of treatment It relates to a method for preventing, ameliorating or treating cancer, including.
  • an effective amount of the oligonucleotide, expression vector or transformed host cell provided by the present invention is administered to a subject in need of treatment. It relates to a method for preventing, ameliorating or treating cancer metastasis, comprising the steps of.
  • the "subject in need of treatment” means cancer or cancer metastasis, which is symptomatic or suspected, and requires prevention, improvement or treatment of cancer or cancer metastasis by inhibiting the growth or proliferation of cancer or cancer stem cells. It may be an object.
  • the oligonucleotide, expression vector or transformed host cell provided in the present invention can inhibit the proliferation or death of cancer cells or cancer stem cells, or inhibit the stemness of cancer stem cells.
  • the expression of at least one of nanog and OCT4, which are stemness-related markers, is suppressed, and the expression of at least one of CK18 and KRT20, the expression of which is suppressed in cancer stem cells, is increased This can lead to loss of stem cell function.
  • cancer stem cells refers to cancer cells in a comprehensive sense that have the ability to self-renew or differentiate, which is a unique ability of stem cells.
  • cancer refers to or refers to a physiological condition typically characterized by unregulated cell growth in mammals. Cancers to be treated and prevented are melanoma, breast cancer, colorectal cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, and skin cancer depending on the site of occurrence.
  • Cancer stem cells capable of differentiating into these cancer cells exist in 1 to 2% of malignant tumor tissues, and have the characteristic of normal stem cells: self-renewal and pluripotent ability to differentiate into other cells.
  • self-renewal and pluripotent ability to differentiate into other cells have the characteristic of normal stem cells: self-renewal and pluripotent ability to differentiate into other cells.
  • self-regulatory function which increases the number of cells by activation of cell division and differentiates itself into malignant tumor cells.
  • cancer stem cells Since the existence of cancer stem cells in leukemia was revealed in 1997 (Blood, 1997), breast cancer (PNAS, 2003), brain tumor (Nature, 2004), prostate cancer (Cancer Res, 2005), colorectal cancer (Nature) , 2007) and melanoma (Nature, 2008) also provided evidence of the presence of cancer stem cells. A small number of cancer stem cells contained in tumors have emerged as the main cause of tumor malignancy, anticancer resistance, and recurrence.
  • Cancer stem cells have markers that distinguish them from other cancer cells, and various cancer stem cell markers specific to cancer are known as cancer stem cell markers as shown in Table 1 below. have.
  • the cancer stem cells that are the target of growth inhibition may include all of the above-listed cancer stem cells, but in particular may be breast cancer stem cells, melanoma stem cells, lung cancer stem cells or colorectal cancer stem cells.
  • the above-described cancer stem cells constantly self-renew, can make tumors with a small number of less than a thousand cells in an experimental animal model, and have the ability as malignant tumor cells.
  • chemotherapy and radiation therapy which are cancer treatments
  • the removal of cancer stem cells is increasingly recognized as a barometer that can measure the success or failure of cancer treatment.
  • cancer can recur from the remaining cancer stem cells even if cancer cells are killed using various existing treatment methods such as surgery, radiation therapy, and chemotherapy.
  • interest in chemotherapy targeting cancer stem cells having the ability to regenerate tumors and development of a treatment protocol for treating cancer based on the chemotherapy is increasing.
  • cancer stem cells in normal tissues regulate cell growth and differentiation by a self-renewal mechanism, but cancer stem cells are affected by tumor microenvironmental factors around tumor cells, resulting in abnormal self-renewal and It is suggested that by activating the maintenance pathway, it rapidly accumulates, becomes malignant, acquires resistance to chemotherapy, and ultimately causes cancer recurrence.
  • a detailed study of the mechanism of interaction with the entity of the tumor microenvironmental factors that control the accumulation and maintenance of cancer stem cells has not yet been conducted.
  • prevention may include, without limitation, any action that blocks cancer symptoms or suppresses or delays cancer symptoms using the pharmaceutical composition of the present invention.
  • treatment may include, without limitation, any action in which cancer symptoms are improved or beneficial using the pharmaceutical composition of the present invention.
  • oligonucleotide, expression vector, transformant or pharmaceutical composition of the present invention may be additionally administered in combination with other anticancer agents, thereby further enhancing the growth inhibitory effect on cancer cells and cancer stem cells.
  • the anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, da satinib, estramustine, gemtuzumab ozogamicin, ibritumomab tuccetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, al
  • the oligonucleotide, expression vector, transformant or pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the oligonucleotides, expression vectors, transformation
  • the body or pharmaceutical composition may be characterized in that it targets humans.
  • composition for preventing, improving or treating degenerative neurodegenerative diseases comprising the oligonucleotide, expression vector or transformed host cell provided in the present invention as an active ingredient.
  • the composition for preventing, improving or treating neurodegenerative diseases may be used for various purposes, such as pharmaceutical compositions or food compositions.
  • it relates to a method for preventing or treating a neurodegenerative disease, comprising administering to a target subject an effective amount of the oligonucleotide, expression vector or transformed host cell provided by the present invention.
  • the "target individual” means an individual who has or has a high probability of developing a neurodegenerative disease.
  • the neurodegenerative diseases include stroke, stroke, memory loss, memory impairment, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob's disease, Huntington's disease and Lou Gehrig's disease. It may be selected from the group consisting of, but is not limited thereto.
  • composition for preventing, improving or treating an immune-related disease comprising the oligonucleotide, expression vector or transformed host cell provided by the present invention as an active ingredient.
  • the composition for preventing, improving or treating immune-related diseases can be used for various purposes, such as pharmaceutical compositions, cosmetic compositions, and food compositions.
  • a method for preventing, ameliorating or treating an immune-related disease comprising administering an effective amount of the oligonucleotide, expression vector or transformed host cell provided by the present invention to a target subject. it's about
  • the "target individual” means an individual who has or is highly likely to develop an immune-related disease.
  • the immune-related disease is Behcet's disease, polymyositis/dermatomyositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary liver cirrhosis, dermatomyositis, Goodpeitzer syndrome, autoimmune meningitis, Sjogren's syndrome , systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, Crohn's disease, insulin-dependent diabetes mellitus, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves disease, Guillain-Barré syndrome, Hashimoto disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumato
  • composition for preventing, improving or treating a wound comprising the oligonucleotide, expression vector or transformed host cell provided by the present invention as an active ingredient.
  • the composition for preventing, improving or treating wounds can be used for various purposes such as pharmaceutical compositions, cosmetic compositions, external preparations for skin, food compositions, etc. due to the skin wound healing activity.
  • it relates to a method for preventing, ameliorating or treating a wound, comprising administering an effective amount of an oligonucleotide, an expression vector, or a transformed host cell provided by the present invention to a target subject. .
  • the "target individual” refers to an individual having a skin injury or a high probability of occurrence.
  • the wounds are wounds, bedsores, burns, abrasions, puncture ulcerative wounds, cuts, chronic skin wounds caused by active oxygen, bruises, cuts, cuts in the throat or oral mucosa, lacerations, diabetic ulcers, lower extremity ulcers, hypertension It may be selected from the group consisting of ischemic ulcers, venous ulcers and foot ulcers, but is not limited thereto.
  • composition for improving skin comprising the oligonucleotide, expression vector or transformed host cell provided in the present invention as an active ingredient.
  • the composition for improving skin can be used for various purposes, such as pharmaceutical compositions, cosmetic compositions, external preparations for skin, food compositions, etc. due to the skin condition improvement activity.
  • it relates to a method for improving skin, comprising administering to a target subject an effective amount of the oligonucleotide, expression vector or transformed host cell provided by the present invention.
  • the "target subject” means an individual in need of improvement of skin conditions such as skin moisturizing, skin whitening, skin elasticity improvement, skin regeneration, wrinkle improvement, or anti-aging.
  • the skin improvement refers to a function of improving skin conditions such as skin moisturizing, skin whitening, skin elasticity improvement, skin regeneration, wrinkle improvement, or anti-aging, but is not limited thereto.
  • the composition for improving skin can be very usefully used as a composition for cosmetic or therapeutic purposes, more specifically, a composition for filler injection due to the skin condition improvement activity, and as a specific example, A composition for filling or replacement, a composition for filling wrinkle, remodeling of the face or an increase in lip volume, rejuvenation of the skin by mesotherapy It can be usefully used as a composition for use in rehydration treatment.
  • the oligonucleotide, expression vector, host cell, or pharmaceutical composition of the present invention is not limited thereto, but oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterilizations, respectively, according to conventional methods. It may be formulated in the form of an injection solution and used.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, fragrances, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, pain relief
  • a topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
  • the route of administration of the oligonucleotide, expression vector, host cell or pharmaceutical composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the oligonucleotide, expression vector, host cell or pharmaceutical composition of the present invention may contain the activity, age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug formulation, and the specific compound to be prevented or treated of the specific compound used. It may vary depending on several factors including the severity of the disease, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art. and may be administered at 0.0001 to 50 mg/kg or 0.001 to 50 mg/kg per day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • an expression vector containing the oligonucleotide of the present invention specifically contains 0.01 to 500 mg, more specifically 0.1 to 300 mg, and in the case of a recombinant virus containing the miRNA of the present invention, specifically 10 3 ⁇ Contains 10 12 IU (10 to 10 10 PFU), more specifically 10 5 to 10 10 IU, but is not limited thereto.
  • a host cell transformed with the expression vector of the present invention it specifically contains 10 3 to 10 8 , and more specifically contains 10 4 to 10 7 , but is not limited thereto.
  • the effective dose of the expression vector containing the oligonucleotide of the present invention or the composition containing the transformed host cell as an active ingredient is 0.05 to 12.5 mg/kg in the case of the vector per kg body weight, and 10 in the case of the recombinant virus. 7 to 10 11 virus particles (10 5 to 10 9 IU)/kg, 10 3 to 10 6 cells/kg for cells, specifically 0.1 to 10 mg/kg for vector, 10 for recombinant virus 8 to 10 10 particles (10 6 to 10 8 IU)/kg, and 10 2 to 10 5 cells/kg in the case of cells, and may be administered 2-3 times a day.
  • the composition as described above is not necessarily limited thereto, and may vary depending on the condition of the patient and the degree of onset of the disease.
  • Suitable delivery reagents for administration in combination with the oligonucleotide of the present invention include Mirus Transit TKO lipophilic reagent, LipoTrust SR, lipofectin, lipofectamine, cellfectin. ) or polycations (eg poly lysine), liposomes, collagen or atelocollagen.
  • a preferred delivery reagent is a liposome.
  • the liposome of the present invention can assist delivery of oligonucleotides to specific tissues such as retina or tumor tissue, and can also increase the half-life of the oligonucleotides in blood.
  • Liposomes suitable for use in the present invention are formed from standard vesicle-forming lipids and are generally neutral or negatively charged phospholipids and sterols such as cholesterol. ) is included. The selection of lipids is usually determined in consideration of factors such as the size of a desired liposome and the half-life of the liposome in blood circulation.
  • a variety of methods for preparing liposomes are known, see, eg, Szoka et al., Ann Rev Biophys Bioeng 1980, 9:467; US Pat. No. 4,235,871; No. 4,501,728; 4,837,028; No. 5,019,369 is incorporated herein by reference in its entirety.
  • the expression vector expressing the oligonucleotide of the present invention is, directly or, Mirus Transit LT1 fat-soluble reagent, LipoTrustTMSR, lipofectin, lipofectamine, cellfectin (cellfectin), polycation (polycation) ( For example, poly lysine) or ribosomes or collagen, atelocollagen, etc. may be administered in combination with an appropriate delivery reagent.
  • Methods of delivering a recombinant viral vector expressing an oligonucleotide of the present invention to a cancer region of a patient are within the skill of the art.
  • the oligonucleotides of the present invention may be administered to a subject by any method suitable for delivery of the oligonucleotides to a cancer region.
  • the oligonucleotides can be administered by gene gun, electroporation, or other suitable parenteral or enteral route of administration.
  • suitable enteral administration routes include oral, rectal or intranasal delivery.
  • suitable parenteral routes of administration include intravenous administration (eg, intravenous bolus injection, intravenous infusion), intra-arterial bolus injection, and intravenous infusion (intravenous injection).
  • peri- and intra-tissue injections eg peri- and intra-tumoral injections, intra-retinal injections or sub-retinal injections
  • subcutaneous injections or subcutaneous injections deposition such as by means of an osmotic pump
  • direct treatment around the area or site of cancer such as a catheter or other means of installation (eg, retinal pellet) , suppositories or implants containing porous, non-porous or gelatinous materials), and inhalation.
  • Injection or injection of oligonucleotides or expression vectors is preferably administered to or around the cancer site. do.
  • the oligonucleotide of the present invention may be administered in a single dose or in multiple doses. Where the oligonucleotides of the present invention are to be infused, the infusion may be administered by a single sustained dose or by multiple infusion. Injection of the drug directly into the tissue may be performed at or around the cancer site; at or around a nerve; blood; at or around the wound; or the area where the skin is to be improved; etc. are preferable. Multiple injections to the site are particularly preferred.
  • the cosmetic composition includes lotion, nutritional lotion, nutritional essence, massage cream, cosmetic bath water additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream, Suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, depilatory makeup, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath soap , water soap, beauty soap, shampoo, hand sanitizer (hand cleaner), medicated soap, medical, cream soap, facial wash, body cleaner, scalp cleaner, hair rinse, cosmetic soap, tooth whitening gel, toothpaste, etc.
  • the composition of the present invention may further include a solvent or an appropriate carrier, excipient or diluent commonly used in the preparation of cosmetic compositions.
  • the type of solvent that can be further added to the cosmetic composition of the present invention is not particularly limited, but for example, water, saline, DMSO, or a combination thereof may be used, and as a carrier, excipient or diluent, purified water, oil, wax , fatty acids, fatty alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, and the like.
  • it may include a whitening agent, a moisturizer, a vitamin, a sunscreen, a perfume, a dye, an antibiotic, an antibacterial agent, an antifungal agent.
  • Hydrogenated vegetable oil castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, and avocado oil may be used as the oil.
  • the wax beeswax, spermaceti, carnauba, candelilla, montan, ceresin, liquid paraffin, and lanolin may be used. can be used
  • fatty acid stearic acid, linoleic acid, linolenic acid, and oleic acid
  • fatty acid alcohol cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, and hexadecanol
  • fatty acid ester isopropyl myristate, isopropyl palmitate, and butyl stearate may be used.
  • surfactant cationic surfactants, anionic surfactants and nonionic surfactants known in the art can be used, and surfactants derived from natural products are preferred as far as possible.
  • it may include a desiccant, a thickener, an antioxidant, etc. widely known in the cosmetic field, and the types and amounts thereof are as known in the art.
  • the food composition of the present invention may be prepared in the form of various foods, for example, beverages, gums, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, and the like. Since the food composition of the present invention is composed of a plant extract having little toxicity and side effects, it can be safely used even when taken for a long period of time for prophylactic purposes.
  • the amount may be added in a proportion of 0.1 to 50% of the total weight.
  • the food composition when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do.
  • monosaccharides such as glucose
  • disaccharides such as fructose
  • polysaccharides such as sucrose
  • common sugars such as dextrin and cyclodextrin
  • sugar alcohols such as xylitol, sorbitol and erythritol
  • flavoring agent examples include natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners , pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • These components may be used independently or in combination.
  • the proportion of these additives is not critical, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the composition of the present invention.
  • the oligonucleotide provided by the present invention can be stably introduced into the human body to effectively inhibit the growth of cancer cells to prevent and/or treat cancer, and furthermore, to prevent cancer resistance, metastasis and recurrence.
  • the oligonucleotide provided by the present invention can effectively prevent, improve or treat neurodegenerative diseases.
  • the oligonucleotide provided by the present invention can be used for various immune-related diseases related thereto by effectively suppressing an immune response.
  • the oligonucleotide provided by the present invention has excellent wound healing or wound healing promoting activity by promoting cell migration to a wound site.
  • the oligonucleotide provided in the present invention has excellent skin permeability and has excellent skin improvement effects such as skin moisturizing, skin whitening, skin elasticity improvement, skin regeneration, anti-wrinkle improvement, and anti-aging when absorbed, as well as irritation or irritation to the skin. It has no side effects and is safe.
  • FIG. 1 is a graph showing the results of confirming the survival rate of lung cancer cells after transforming lung cancer cells with oligonucleotides of hsa-miR-503-3p (PSI-501) and its analogs 1 to 23 in Experimental Example 1. .
  • FIG. 2 is a graph showing the results of confirming the survival rate of lung cancer cells after transforming lung cancer cells with oligonucleotides of hsa-miR-503-3p (PSI-501) and its analogs 24 to 31 in Experimental Example 1. .
  • FIG. 3 shows the size of a tumor when hsa-miR-503-3p (PSI-501) and its analogues 28 and 31 oligonucleotides were administered in an animal model transplanted with lung cancer cells in Experimental Example 3.
  • One object of the present invention is to provide a novel oligonucleotide that is an analog of hsa-miR-503-3p, hsa-miR-328-3p, and hsa-miR-6514-5p.
  • Oligoribonucleotide types base sequence hsa-miR-503-3p-analog 1 cggguauuguuuccgcugccagg (SEQ ID NO: 7) hsa-miR-503-3p-analog 2 gcgguauuguuuccgcugccagg (SEQ ID NO: 8) hsa-miR-503-3p-analog 3 ggcguauuguuuccgcugccagg (SEQ ID NO: 9) hsa-miR-503-3p-analog 4 gggcuauuguuuccgcugccagg (SEQ ID NO: 10) hsa-miR-503-3p-analog 5 ggggaauuguuuccgcugccagg (SEQ ID NO: 11) hsa-miR-503-3p-analog 6 gggguuuuguuuccgcugccagg (SEQ ID NO: 12) hsa-mi
  • the effect of the oligonucleotide on lung cancer cell lines was confirmed, and the results are shown in FIGS. 1 and 2 .
  • the lung cancer cell line was analyzed using NCI-H460 (ATCC, HTB-177) and RPMI-1640 (Hyclone, USA) containing 10% FBS (Hyclone, USA) and 1% penicillin/streptomycin (WELGENE, Korea) cultured in Cells were cultured in 5% CO 2 ,37° C. cell incubator. Then, 3000 cells of NCI-H460 cells were dispensed in a 96-well plate, and cultured overnight (over-night) followed by transformation (transfection).
  • hsa-miR-503-3p 20 nM of hsa-miR-503-3p (PSI-503) was transformed into cells using Lipofectamine 2000 (Invitrogen, CA). After 72 hours of treatment with each oligonucleotide, the amount of cells was measured using a cell counting kit-8 (Dojindo, Japan), and the absorbance was measured after reaction at 450 nm wavelength for 1 hour.
  • the average drug sensitivity was measured in the NCI-H460 cell line, and the results are shown in Table 3. Specifically, the average of 50% growth inhibition values (GI50) in the NCI-H460 cell line was calculated. Data are presented as molar concentrations representing GI50 values. These values were determined using the optimal concentration range for each endpoint. Percent growth inhibition was calculated using 7 absorbance measurements [time zero (Tz), growth control (C), growth test at 5 drug concentration levels (Ti)] as follows:
  • a lung cancer cell line NCI-H460
  • Cells to be used for the test were thawed, placed in a cell culture flask, and cultured in an incubator at 37° C., 5% CO 2 (incubator MCO-170M, Panasonic, Japan).
  • the cells cultured on the day of cell line transplantation were placed in a centrifuge tube and recovered, and then centrifuged (125 x g, 5 min) to discard the supernatant and prepare a cell suspension (5 ⁇ 10 7 cells/mL) with PBS. .
  • the cell line was transplanted. After measuring the body weight the next day after the completion of the acclimatization period , it was dispensed with a cell suspension (1 ⁇ 10 7 cells/0.05 mL) prepared for healthy animals, and 0.05 mL Matrigel matrix phenol red-free (Matrigel matrix phenol red-free) ( 356237, BD, USA) was added and the prepared solution was filled in a disposable syringe, and 0.1 mL/head was administered subcutaneously to the right back of the animal. The number of transplanted cells was 5x10 6 cells/head. After transplantation of the cell line, general symptoms were observed once daily during the engraftment and growth period.
  • Matrigel matrix phenol red-free Matrigel matrix phenol red-free
  • the tumor volume was measured for an animal without any abnormality, and 60 individuals with an average tumor volume of about 80 to 120 mm 3 were selected.
  • the selected animals were divided into 6 groups, 10 animals per group, to be as uniform as possible based on the tumor volume and body weight.
  • test substance was administered intratumorally, and intratumoral administration was administered using an insulin syringe (BD, U.S.A.) (QD).
  • BD insulin syringe
  • QD insulin syringe
  • analog 31 had a particularly remarkable tumor suppressive effect compared to the control group and other examples.
  • the present invention relates to novel miRNA analogs and various uses thereof.
  • SEQ ID NO: 4 seed sequence of hsa-miR-503-3p
  • SEQ ID NO: 5 seed sequence of hsa-miR-328-3p
  • SEQ ID NO: 6 seed sequence of hsa-miR-6514-5p
  • SEQ ID NO: 8 hsa-miR-503-3p analog
  • SEQ ID NO: 12 hsa-miR-503-3p analog
  • SEQ ID NO: 17 hsa-miR-503-3p analog
  • SEQ ID NO: 18 hsa-miR-503-3p analog
  • SEQ ID NO: 26 hsa-miR-503-3p analog
  • SEQ ID NO: 27 hsa-miR-503-3p analog
  • SEQ ID NO: 28 hsa-miR-503-3p analog
  • SEQ ID NO: 36 hsa-miR-503-3p analog
  • SEQ ID NO: 48 hsa-miR-328-3p analog
  • SEQ ID NO: 65 hsa-miR-6514-5p analog
  • SEQ ID NO: 68 hsa-miR-6514-5p analog
  • SEQ ID NO: 70 hsa-miR-6514-5p analog
  • SEQ ID NO: 72 hsa-miR-6514-5p analog
  • SEQ ID NO: 75 hsa-miR-6514-5p analog
  • SEQ ID NO: 80 hsa-miR-6514-5p analog

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Abstract

La présente invention concerne un oligonucléotide, qui est un analogue de hsa-miR-503-3p, de hsa-miR-328-3p ou de hsa-miR-6514-5p. L'oligonucléotide selon la présente invention est introduit de manière stable dans le corps humain pour inhiber efficacement la prolifération des cellules cancéreuses, ce qui permet de prévenir et/ou de traiter le cancer. De plus, l'oligonucléotide a une action de cicatrisation des plaies ou favorise la cicatrisation des plaies et, lorsqu'il est administré dans la peau, il présente d'excellents effets d'amélioration de la peau, par exemple en termes d'hydratation de la peau, de blanchiment de la peau, d'amélioration de l'élasticité de la peau, de régénération de la peau, d'atténuation des rides et d'effet anti-âge, tout en ne provoquant pas d'irritation de la peau ni d'effets secondaires et en ne présentant aucun danger.
PCT/KR2020/007578 2020-06-11 2020-06-11 Nouveaux analogues de miarn et leurs utilisations WO2021251526A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009532392A (ja) * 2006-04-03 2009-09-10 サンタリス ファーマ アー／エス ａｎｔｉｍｉＲＮＡアンチセンスオリゴヌクレオチドを含む医薬組成物
JP2010154843A (ja) * 2008-06-27 2010-07-15 Keio Gijuku バイオマーカーとしてのマイクロｒｎａを用いた婦人科がんの診断・治療選択
US20150352055A1 (en) * 2013-01-24 2015-12-10 Pierre Fabre Medicament S.A.S. Composition comprising an encapsulated antagomir
KR20180137435A (ko) * 2017-06-16 2018-12-27 (주)프로스테믹스 암의 예방 또는 치료용 약학적 조성물
KR20190062159A (ko) * 2017-11-27 2019-06-05 (주)프로스테믹스 miRNA를 포함하는 상처 치료 또는 피부 개선용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009532392A (ja) * 2006-04-03 2009-09-10 サンタリス ファーマ アー／エス ａｎｔｉｍｉＲＮＡアンチセンスオリゴヌクレオチドを含む医薬組成物
JP2010154843A (ja) * 2008-06-27 2010-07-15 Keio Gijuku バイオマーカーとしてのマイクロｒｎａを用いた婦人科がんの診断・治療選択
US20150352055A1 (en) * 2013-01-24 2015-12-10 Pierre Fabre Medicament S.A.S. Composition comprising an encapsulated antagomir
KR20180137435A (ko) * 2017-06-16 2018-12-27 (주)프로스테믹스 암의 예방 또는 치료용 약학적 조성물
KR20190062159A (ko) * 2017-11-27 2019-06-05 (주)프로스테믹스 miRNA를 포함하는 상처 치료 또는 피부 개선용 조성물

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