Development of a guideline for designing lipid-conjugated antisense oligonucleotide

2014 Fiscal Year Final Research Report

• Project/Area Number: 25871235
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical genome science; Drug development chemistry
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: WADA Shunsuke 独立行政法人国立循環器病研究センター, 研究所, 流動研究員 (40631297)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: アンチセンス核酸 / コレステロールコンジュゲート / リンカー / 2',4'-BNA/LNA

Outline of Final Research Achievements

Cholesterol conjugation is an way to deliver the antisense oligonucleotides (ASOs) specifically to the liver. However most of the cholesterol-conjugated ASO could not improve the inhibition of target RNA compared to that of unconjugated ASO because cholesterol-conjugated ASOs mainly accumulated in non-parenchymal cells like kuppfer cells. We tried to optimize the lipid-conjugation by focusing the attention on linker chemistry. We prepared a variety of linkers to conjugate the cholesterol to anti-Pcsk9 ASOs and examined their effects on the pharmacological parameters.
Hepatic accumulation and cell tropism of the cholesterol-conjugated ASO were largely depended on their linker chemistry. Our designed cleavable linker which has phosphodiester bond between linker and cholesterol improved the inhibitory effect of ASO, indicating the importance of removing the conjugation. Our findings will provide a guideline for designing molecular conjugation of AONs.

Free Research Field

核酸創薬