Abstract
Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.
Highlights
Myotonic Dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy which affects 1 in 8,000 people [1]
As cyclin-dependent kinase 12 (CDK12) is not required at the start of transcription and its inhibition does not result in global transcriptional arrest, alongside our data that shows continuous treatment is not necessary for beneficial effects, it may be suitable as a target for long term DM1 treatment
Our results show that genetic knockdown of CDK12, or treatment with inhibitor, leads to reduced numbers of nuclear foci, which could be due to two possible mechanisms: reduced production of the mutant transcripts or their increased degradation
Summary
Myotonic Dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy which affects 1 in 8,000 people [1]. The expanded repeat is transcribed, and despite being correctly spliced, the repeat expansion transcripts remain sequestered in the nucleus forming distinct foci [5,6,7]. These foci interact with cellular proteins, such as muscleblind-like splicing regulator 1 (MBNL1), a key splicing regulator, which in turn leads to downstream splicing abnormalities [8, 9]. Additional molecular pathways are thought to be affected by the toxic RNA, including repeat associated non-AUG (RAN) translation and inhibition of translation [11, 12]
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