Development of novel HDO that enables regulation of gene expression in CNS by systemic administration

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05221
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAGATA Tetsuya 東京医科歯科大学, 大学院医歯学総合研究科, 特任准教授 (50362976)
• Research Collaborator: MIYATA Kanjiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 核酸医薬 / 神経変性疾患 / ヘテロ核酸 / 中枢移行性

Outline of Final Research Achievements

By systemic administration of new type of hetero duplex oligonucleotide (HDO), gene knockdown in the brain and spinal cord was observed. Moreover, the effect was enhanced by multiple administration, and we also confirmed that there was dose dependency. Subcutaneous administration was also effective in the central nervous system (CNS). On the other hand, no effect was observed at all by systemic administration of single stranded ASO. So far, gene knockdown effects in CNS by systemic administration of any oligonucleotide have not been demonstrated. We also found that the dynamics of HDO in the blood is significantly different from that of single-stranded ASO. Furthermore, differences in binding proteins and protein binding profiles of HDO in blood were also identified.

Free Research Field

核酸医薬　神経変性疾患

Academic Significance and Societal Importance of the Research Achievements

遺伝性神経難病に対する核酸を用いた治療法は、その標的遺伝子への特異性の高さや標的の多さなどから有望な治療法として、期待されており、すでに承認済みの医薬品があり、かつ多くの臨床試験が進んでいる。一方で投与経路は髄腔投与に限られており、長期投与・肉体的負担などが懸念されている。核酸の動態から脳血管関門(BBB)を超えることは非常に難しいと考えられていた。本技術において、静脈投与で脳および脊髄での遺伝子抑制することを確認した意義は非常に高い。本技術は粗削りながら、今後の開発により大きな成長が期待できる。