Elucidation of intracerebral distribution of CAG repeat binding molecules after intranasal administration and verification of effect on repeat contraction.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19049
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: Osaka University
• Principal Investigator: Shibata Tomonori 大阪大学, 産業科学研究所, 招へい教員 (80711960)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: 経鼻投与 / CAGリピート / ハンチントン病 / 全脳イメージング / CAGリピート結合分子 / 組織透明化

Outline of Final Research Achievements

Huntington's disease is an incurable disorder in which neurons in the brain striatum are degenerated due to aberrant expansion of CAG repeats. We have found that direct administration of a CAG repeat-binding small molecule (NA) into the brain striatum of a mouse model of Huntington's disease resulted in the contraction of aberrantly expanded CAG repeats. Because of the limited transfer of NA from the blood to the brain, NA administration is limited to the invasive method of direct administration to the brain striatum. In this study, we analyzed the drug delivery pathway and the intracerebral distribution of an NA derivative after noninvasive intranasal administration by three-dimensional whole-brain imaging using a combination of tissue clearing and light sheet fluorescence microscopy.

Free Research Field

核酸化学

Academic Significance and Societal Importance of the Research Achievements

NAは、ハンチントン病のマウスモデルにおいて異常に伸長したCAGリピートを短縮する画期的な低分子である。将来のハンチントン病治療においては、NAを脳内へと送達すること重要な課題であり、本研究により明らかとなった経鼻投与後のNAの脳内動態はNAの治療効果を検証していく上で重要な知見になると考えられる。