Therapeutic targeting expanded DNA using cyclic pyrrole-imidazole polyamide in CAG/CTG triplet repeat neurological diseases.

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  • CAG/CTGトリプレットリピート病における環状ピロール-イミダゾールポリアミドを用いた伸長DNA標的治療法の開発

Abstract

<p>Expanded CAG/CTG triplet repeats are causal in a number of human neurological disorders, and can be classified into two types according to the location of the repeats; 1) The CAG repeat expansion in coding regions, including Huntington&apos;s disease (HD), spinocerebellar ataxia (SCA) type-1, 2, 3, 6, 7, and 17, spinal and bulbar muscular atrophy (SBMA), and dentatorubral pallidoluysian atrophy (DRPLA). 2) The CAG/CTG repeat expansion in noncoding, especially in 3&apos; untranslated regions (3&apos;-UTRs), including myotonic dystrophy type 1 (DM1) and SCA8. Here, we show a DNA targeting compound, cyclic Pyrrole-Imidazole Polyamide (cPIP) can suppress the pathogenesis of coding and noncoding CAG/CTG repeat expansion diseases. cPIP bound to duplex as well as hairpin CAG/CTG DNA specifically, inhibiting the RNA polymerase II passage in a repeat length dependent manner in vitro. cPIP inhibits the CAG/CTG repeat-derived mRNA transcript, result in reduction of pathogenic CUG-RNA foci and polyglutamine (polyQ) accumulations. This study presents a candidate compound for targeting pathogenic expanded CAG/CTG repeat DNA, demonstrating the concept of lowering levels of repeat disease-causing RNAs and proteins.</p>

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