A Selective Alkylating Agent for CTG Repeats in Myotonic Dystrophy Type 1
Disease intervention at the DNA level generally has been avoided because of off-target effects. Recent advances in genome editing technologies using CRISPR-Cas9 have opened a new era in DNA-targeted therapeutic approaches. However, delivery of such systems remains a major challenge. Here, we report...
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Published in | ACS chemical biology Vol. 17; no. 5; pp. 1103 - 1110 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
20.05.2022
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Online Access | Get full text |
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Summary: | Disease intervention at the DNA level generally has been avoided because of off-target effects. Recent advances in genome editing technologies using CRISPR-Cas9 have opened a new era in DNA-targeted therapeutic approaches. However, delivery of such systems remains a major challenge. Here, we report a selective DNA-modifying small molecule that targets a disease-specific structure and mismatches involved in myotonic dystrophy type 1 (DM1). This ligand alkylates T–T mismatch-containing hairpins formed in the expanded CTG repeats (d(CTG)exp) in DM1. Ligand alkylation of d(CTG)exp inhibits the transcription of d(CAG·CTG)exp, thereby reducing the level of the toxic r(CUG)exp transcript. The bioactivity of the ligand also included a reduction in DM1 pathological features such as disease foci formation and misregulation of pre-mRNA splicing in DM1 model cells. Furthermore, the CTG-alkylating ligand may change the d(CAG·CTG)exp repeat length dynamics in DM1 patient cells. Our strategy of linking an alkylating moiety to a DNA mismatch-selective small molecule may be generally applicable to other repeat expansion diseases such as Huntington’s disease and amyotrophic lateral sclerosis. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1554-8929 1554-8937 |
DOI: | 10.1021/acschembio.1c00949 |