Development of increasing functional HDL-C using antisense oligonucleotides as innovative therapy

• Project/Area Number: 23591109
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: IWAMOTO Noriyuki 独立行政法人国立循環器病研究センター, 研究所, 客員研究員 (70534709)
• Co-Investigator(Kenkyū-buntansha): 斯波 真理子 独立行政法人国立循環器病研究センター, その他部局等, その他 (70271575)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: HDL / ABCA1 / 核酸医薬

Research Abstract

The objective of this basic research is to analyze whether or not innovative antisense oligonucleotides targeted specific molecular gene would be candidate of increasing serum HDL-cholesterollevel through the ABCA1/apoA-I pathway. We previously demonstrated that transcription factor AP-2 negatively regulates the ATP-binding cassette A1 (ABCA1) gene through its Ser-phosphorylation by protein kinase PKD which is a common modulator of the DNA binding activity of AP-2 through their phosphorylation for negative regulation of the ABCA in genes expression. The Antisense oligoniculeotide modified BNA is so innovative that have stronger effective compared to previous one.
In this study, we demonstrated that the PKD specific targeted antisense could increase ABCA1 mRNA levels in liver in vitro and in vivo, which result in raising serum HDL-C level in vivo. To further develop this strategy, we need more experiments to figure out the value of efficacy and safety using oligonucleotides therapy

Research Products

• [Journal Article] Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: a common pathway to the ABCA1 gene regulation (2011)
  • Author(s): Iwamoto N, Yokoyama S
  • Journal Title: Atherosclerosis Volume: 216(1) Pages: 90-6
  • Peer Reviewed
• [Journal Article] Involvement of protein kinase D in phosphorylation and increase of DNA binding of activator protein 2 alpha to downregulate ATP-binding cassette transporter A1 (2008)
  • Author(s): Iwamoto N, Abe-Dohmae S, Lu R, Yokoyama S
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 28(12) Pages: 2282-7
  • Peer Reviewed
• [Journal Article] ATP-binding cassette transporter A1 gene transcription is downregulated by activator protein 2alpha. Doxazosin inhibits activator protein 2alpha and increases high-density lipoprotein biogenesis independent of alpha1-adrenoceptor blockade (2007)
  • Author(s): Iwamoto N, Abe-Dohmae S, Ayaori M, Tanaka N, Kusuhara M, Ohsuzu F, Yokoyama S
  • Journal Title: Circ Res Volume: 20;101(2) Pages: 156-65
  • Peer Reviewed