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Development of novel therapeutic approach using gene delivery method for treatment of cardiovascular disease

Antisense and siRNA, modified with BNA/LNA, have been developed under the collaboration with Professor Satoshi Obika (Univ. of Osaka) for the treatment of severe hypercholesterolemia, especially FH. The novel nucleic acid drugs have been shown to have extremely high activity in vivo because of their very high resistance activity against nuclease and extremely high affinity to the target RNA. The project is now going on to develop cholesterol lowering drugs by suppression of genes related to cholesterol metabolism using BNA/LNA.

References

  1. Yamamoto T, Obika S, Nakatani M, Yasuhara H, Wada F, Shibata E, Shibata MA, Harada-Shiba M: Locked nucleic acid antisense inhibitor targeting apolipoprotein C-III efficiently and preferentially removed triglyceride from large VLDL particles from murine plasma, European Journal of Pharmacology, in press
  2. Nagasaki Y, Yamazaki T, Kikuchi A, Harada-Shiba M: Elevated atherogenic indexfollowing oral administration of quaternized polyamine nanogels, Colloids and Surfaces, in press
  3. Kang JH, Tachibana Y, Obika S, Harada-Shiba M, Yamaoka T: Efficient reduction of serum cholesterol by combining a liver-targeted gene delivery system with chemically modified apolipoprotein B siRNA: J Control Release, 2012; 163(2): 119-124.
  4. Yamamoto T, Yasuhara H, Wada F, Harada-Shiba M, Imanishi T, Obika S: Superior silencing by 2',4'-BNANC-based short antisense oligonucleotides compared to 2',4'-BNA/LNA-based apolipoprotein B antisense inhibitors: J Nucleic Acids, 2012; 707323.
  5. Wada S, Obika S, Shibata MA, Yamamoto T, Nakatani M, Yamaoka T, Torigoe H, Harada-Shiba M: Development of a 2',4'-BNA/LNA based siRNA for dyslipidemia and assessment of the effects of its chemical modifications in vivo: Molecular Therapy - Nucleic Acids, 2012; 1, e45: 1-15.
  6. Yamamoto T, Harada-Shiba M, Nakatani M, Wada S, Yasuhara H, Narukawa K, Sasaki K, Shibata MA, Torigoe H, Yamaoka T, Imanishi T, Obika S: Cholesterol-Lowering Action of BNA-based Antisense Oligonucleotides Targeting PCSK9 in Atherogenic Diet-Induced Hypercholesterolemic Mice: Molecular Therapy- Nucleic Acid, 2012; 1, e22: 1-11.
  7. Kang J, Tachibana Y, Kanata W, Mahara A, Harada-Shiba M, Yamaoka T : Liver-targeted siRNA delivery by polyethyleneimine(PEI)-pullulan carrir. Bioorg Med Chem, 2010; 18: 3946-3950.
  8. Watanabe K, Harada-Shiba M, Suzuki A, Gokuden R, Kurihara R, Sugao Y, Mori T, Katayama Y, Niidome T: In vivo siRNA delivery with dendritic poly(L-lysine) for the treatment of hypercholesterolemia. Mol Biosyst 5: 1306-1310, 2009.
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