Allele specific inhibition of mutant mRNA expression for repeat expansion disorders

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K15339
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: Nakamori Masayuki 大阪大学, 医学系研究科, 助教 (60630233)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 筋強直性ジストロフィー / ハンチントン病 / リピート病

Outline of Final Research Achievements

Repeat expansion disorders are caused by unstable expansions of tandem repeats, such as CAG or CTG. The transcripts containing the expanded repeat or abnormal protein products can give rise to a toxic gain-of-function by the mutant RNA (e.g. myotonic dystrophy) or mutant protein (e.g. Huntington disease). In this study, we identified small molecules that specifically inhibit transcription of mutant alleles with expanded repeats. These compounds reduced abnormal RNA levels in a cell model for myotonic dystrophy. The lead compound showed treatment effects in a mouse model for repeat expansion disorders. These results indicate that allele specific inhibition of mutant mRNA can be a means to treat repeat expansion disorders.

Free Research Field

神経筋疾患

Academic Significance and Societal Importance of the Research Achievements

リピート病は、そのほとんどが進行性の神経筋変性疾患であり、現在根本的な治療法がない難病である。本研究により、リピート病の原因を根源から断つ、新たな治療アプローチの可能性が示された。また、この治療アプローチは、リピート病のなかでも伸長リピート配列が同一の疾患群全てにおいて治療効果が期待できる。