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

Ketley, Ami; Wojciechowska, Marzena; Ghidelli-Disse, Sonja; Bamborough, Paul; Ghosh, Tushar K.; Morato, Marta Lopez; Sedehizadeh, Saam; Malik, Naveed Altaf; Tang, Zhenzhi; Powalowska, Paulina; Tanner, Matthew K; Billeter‐Clark, Rudolf; Trueman, Rebecca C.; Geiszler, Philippine C.; Agostini, Alessandra; Othman, Othman; Bösche, Markus; Bantscheff, Marcus; Rüdiger, Martin; Mossakowska, Danuta E.; Drewry, David H.; Zuercher, William J.; Thornton, Charles A.; Drewes, Gerard; Uings, Iain; Hayes, Christopher J.; Brook, J. David

doi:10.1126/scitranslmed.aaz2415

Cited by 16 publications

(19 citation statements)

References 70 publications

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“…Interestingly, muscle sodium channel SCN4A transcripts were reduced in DM1 cells and antagomiR-218 treated myotubes compared with healthy controls, thus potentially contributing to DMPK downregulation (Figure S10D). CDK12 inhibitors are also capable of lowering DMPK transcript levels, but in HSA LR mice this was shown to reduce the transcription of the transgene itself, 55 which was not detected in our study.…”

Section: Discussioncontrasting

confidence: 72%

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Cerro-Herreros

González-Martínez

Moreno

et al. 2021

Molecular Therapy - Nucleic Acids

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Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an anta-gomiR-218 molecule using the HSA LR mouse model and patient-derived myotubes. In HSA LR , antagomiR-218 reached 40-60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose-and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target.

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Section: Discussioncontrasting

confidence: 72%

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Cerro-Herreros

González-Martínez

Moreno

et al. 2021

Molecular Therapy - Nucleic Acids

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“…These kinases are important for transcriptional initiation and/or elongation. Cyclin-dependent kinase 12 (CDK12) is a transcriptional kinase comprised of 1490 amino acids, which has recently been shown to play a role in nuclear foci formation in DM1 [7]. It was first discovered in 2001 as a putative element of transcription process [8].…”

Section: The Role Of Cdk12 In the Production Of Dmpk Expansion Transc...mentioning

confidence: 99%

“…The main target of one subset of these kinase inhibitors was identified as CDK12, which provides a novel druggable molecular target for myotonic dystrophy. Ketley et al demonstrated the relationship between CDK12 and the production of mutant DMPK transcripts [7]. CDK12 inhibitors were found to eliminate the nuclear foci in DM cells as well as in the HSA LR mouse model, leading to potentially beneficial effects [7].…”

Section: Cdk12 As a Therapeutic Target For Myotonic Dystrophymentioning

confidence: 99%

Disrupting the Molecular Pathway in Myotonic Dystrophy

Xing

Kumari

Brown

et al. 2021

IJMS

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Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.

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“…By contrast, it has been described in DM5 mice that Celf1 phosphorylation is not affected by deficiency of PKCα or PKCβ and that these transgenic mice show similar disease progression when lacking both isoforms (Kim et al ., 2016). Data also suggest that CELF1 has PKC‐independent effects that are driven by other kinases (Ketley et al ., 2014), such as cyclin‐dependent kinase 12 (CDK12), which was recently identified as an interesting target in DM1 pathogenesis (Ketley et al ., 2020).…”

Section: Signalling Cascades That Contribute To Dm1 Muscle Atrophymentioning

confidence: 99%

“…In fact, as previously mentioned, it was found that STAU1 inhibits MEF2 thus proving that its overexpression in DM1 further impairs the differentiation of skeletal muscle cells (Ravel‐Chapuis et al ., 2014; Parks et al ., 2017). Also, it has recently been shown that CDK12, which is required for the maintenance of genomic integrity during embryonic development (Juan et al ., 2016), is elevated in DM1 cell lines and patient biopsies (Ketley et al ., 2020).…”

Section: Cellular Processes Implicated In Dm1 Muscle Atrophymentioning

confidence: 99%

The hallmarks of myotonic dystrophy type 1 muscle dysfunction

et al. 2020

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Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3′ untranslated region (3′UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind‐like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav‐like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin–proteasome activity, which may also be affected in DM1 by AMP‐activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis‐regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor‐inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non‐coding RNA metabolism, calcium dysregulation, and repeat‐associated non‐ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.

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

Cited by 16 publications

References 70 publications

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Disrupting the Molecular Pathway in Myotonic Dystrophy

The hallmarks of myotonic dystrophy type 1 muscle dysfunction

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