Research ArticleMuscular Dystrophy

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model

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Science Translational Medicine  29 Apr 2020:
Vol. 12, Issue 541, eaaz2415
DOI: 10.1126/scitranslmed.aaz2415

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Muscling in on myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a genetic muscular disorder caused by accumulation of nuclear foci due to CTG repeat expansion in the DMPK gene. Current therapies only target individual symptoms. Now, Ketley et al. set out to identify targets for reducing the accumulation of nuclear foci. The authors showed that cyclin-dependent kinase 12 (CDK12) is increased in muscle biopsies from patients with DM1 and its inhibition with a small molecule reduced the accumulation of nuclear foci and mutant transcripts. In a mouse model of DM1, CDK12 inhibition reduced nuclear foci and improved myotonia. The results suggest that CDK12 might be a good therapeutic target for treating DM1.

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.

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