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PKLR inhibition in the treatment of NAFLD and HCC

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اقرأ أكثر حفظ في قائمتي
  • Publication Date:
    June 15, 2021
  • معلومة اضافية
    • Patent Number:
      11034,960
    • Appl. No:
      16/638927
    • Application Filed:
      August 14, 2018
    • نبذة مختصرة :
      There is provided a medical agent for use in a method of treatment of nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC), wherein the medical agent comprises a polynucleotide and is capable of silencing or knocking out the PKLR gene.
    • Inventors:
      ScandiEdge Therapeutics AB (Johanneshov, SE)
    • Assignees:
      ScandiEdge Therapeutics AB (Johanneshov, SE)
    • Claim:
      1. A method of treating a subject having nonalcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC), said method comprising administering to the subject a therapeutically effective amount of a medical agent comprising a polynucleotide, which medical agent is capable of silencing or knocking out the pyruvate kinase liver and red blood cell (PKLR) gene.
    • Claim:
      2. The method according to claim 1 , wherein the polynucleotide is an RNA molecule.
    • Claim:
      3. The method according to claim 1 , wherein the polynucleotide is an anti sense polynucleotide.
    • Claim:
      4. The method according to claim 1 , wherein the polynucleotide is capable of selective interaction with PKLR DNA or PKLR RNA.
    • Claim:
      5. The method according to claim 1 , wherein the polynucleotide is capable of selective interaction with a sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4.
    • Claim:
      6. The method according to claim 1 , wherein the polynucleotide is capable of selective interaction with a RNA sequence that can be transcribed from a sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4.
    • Claim:
      7. The method according to claim 1 , wherein the polynucleotide comprises a sequence that is at least 75% identical to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8.
    • Claim:
      8. The method according to claim 1 , wherein the medical agent is formulated in a lipid nanoparticle.
    • Claim:
      9. The method according to claim 1 , wherein the polynucleotide is conjugated to GalNAc.
    • Claim:
      10. The method according to claim 9 , wherein the polynucleotide GalNAc conjugate is a trivalent GalNAc conjugate.
    • Claim:
      11. The method according to claim 10 , wherein the polynucleotide GalNAc conjugate comprises more than three GalNAc molecules per polynucleotide.
    • Claim:
      12. The method according to claim 1 , wherein the 5′-phosphate of the polynucleotide is modified.
    • Claim:
      13. The method according to claim 1 , wherein the polynucleotide is phosphorothioate modified.
    • Claim:
      14. The method according to claim 1 , wherein the method comprises a step of detecting expression of the PKLR gene in a liver sample from the subject having the NAFLD or HCC.
    • Claim:
      15. The method according to claim 14 , wherein the liver sample is a liver biopsy.
    • Claim:
      16. The method according to claim 14 , wherein the step of detecting expression of the PKLR gene comprises PCR, RNA-Seq or a micro array.
    • Claim:
      17. The method of claim 1 , wherein the medical agent is administered orally or by subcutaneous injection.
    • Claim:
      18. The method according to claim 2 , wherein the RNA molecule is a siRNA molecule, a miRNA molecule, a guide RNA molecule (gRNA) or an aptamer.
    • Claim:
      19. The method according to claim 3 , wherein the antisense polynucleotide is an antisense oligonucleotide (ASO).
    • Claim:
      20. The method according to claim 5 , wherein the polynucleotide is capable of selective interaction with a sequence selected from SEQ ID NO:2 and 4.
    • Claim:
      21. The method according to claim 6 , wherein the polynucleotide is capable of selective interaction with a RNA sequence that can be transcribed from a sequence selected from SEQ ID NO:2 and 4.
    • Claim:
      22. The method according to claim 9 , wherein the polynucleotide is a GalNAc cluster.
    • Claim:
      23. The method according to claim 12 , wherein the 5′-phosphate of the polynucleotide is modified to 5′-vinylphosphonate.
    • Patent References Cited:
      2011/0212889 September 2011 Oral et al.
      2011/115810 September 2011





    • Other References:
      Krishnan et al. (Cell Systems, 2018 vol. 6:103-115). cited by examiner
      Agren et al. “Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling”, Molecular Systems Biology 10(3):721 (2014) (13 pages). cited by applicant
      International Search Report and Written Opinion corresponding to International Application No. PCT/EP2018/072036 dated Sep. 25, 2018. cited by applicant
      Lee et al. “Network analyses identify liver-specific targets for treating liver diseases”, Molecular Systems Biology 13(8):938 (2017) (15 pages). cited by applicant
      Nair et al. “Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing”, J. Am. Chem. Soc. 136(49):16958-16961 (2014). cited by applicant
      Prakash et al. “Synergistic effect of phosphorothioate, 5′-vinylphosphonate and GaINAc modificaiions for enhancing activity of synthetic siRNA”, Bioorganic & Medicinal Chemistry Letters 26(12):2817-2820 (2016). cited by applicant
    • Primary Examiner:
      Gibbs, Terra C
    • Attorney, Agent or Firm:
      Myers Bigel, P.A.
    • الرقم المعرف:
      edspgr.11034960