Myotonic dystrophy: candidate small molecule therapeutics

Konieczny, Piotr; Selma-Soriano, Estela; Rapisarda, A.; Fernández‐Costa, Juan M.; Pérez-Alonso, Manuel; Artero, Rubén

doi:10.1016/j.drudis.2017.07.011

Cited by 47 publications

(39 citation statements)

References 66 publications

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“…MyoD-transduced DM1 fibroblasts have already been used to test the efficacy of antisense oligonucleotides in reducing ribonuclear foci (54). MBNL is being considered as a target for treating DM1 (55), and the data herein suggest that this target may be less useful for treating DM2. iPSC-CMs have successfully modeled cardiac arrhythmic disorders and serve as a tool for high-throughput and selective drug screening (56).…”

Section: Discussionmentioning

confidence: 89%

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Kim

Barefield

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 89%

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Kim

Barefield

et al. 2019

JCI Insight

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“…Whether ageing is intrinsic to the cells or is a reflection of the cellular response to the ageing environment is under debate. (Seow et al, 2012;reviewed in Overby et al, 2018); Mexiletine (Nguyen and Campbell, 2016); adding muscleblind-like protein 1 (reviewed in Konieczny et al, 2017…”

Section: Satellite Cell Defects In Muscular Dystrophiesmentioning

confidence: 99%

Skeletal muscle in health and disease

Morgan

Partridge

2020

Disease Models &Amp; Mechanisms

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Skeletal muscle fibres are multinucleated cells that contain postmitotic nuclei (i.e. they are no longer able to divide) and perform muscle contraction. They are formed by fusion of muscle precursor cells, and grow into elongating myofibres by the addition of further precursor cells, called satellite cells, which are also responsible for regeneration following injury. Skeletal muscle regeneration occurs in most muscular dystrophies in response to necrosis of muscle fibres. However, the complex environment within dystrophic skeletal muscle, which includes inflammatory cells, fibroblasts and fibro-adipogenic cells, together with the genetic background of the in vivo model and the muscle being studied, complicates the interpretation of laboratory studies on muscular dystrophies. Many genes are expressed in satellite cells and in other tissues, which makes it difficult to determine the molecular cause of various types of muscular dystrophies. Here, and in the accompanying poster, we discuss our current knowledge of the cellular mechanisms that govern the growth and regeneration of skeletal muscle, and highlight the defects in satellite cell function that give rise to muscular dystrophies.

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“…This repeat DNA produces the toxic CUG repeat RNA which forms a complex with the alternative-splicing regulator muscleblind-like protein (MBNL), leading to splicing defects and disease symptoms. Thus, abnormal extended CTG or CUG repeats are considered to be one of the important targets for DM1 and several promising compounds have been developed ( 17 , 18 ). For example, TAT derivatives, which can bind the CTG or CUG repeats, strongly inhibit the transcription or formation of the complex with MBNL ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Selective alkylation of T–T mismatched DNA using vinyldiaminotriazine–acridine conjugate

Onizuka

Usami

Yamaoki

et al. 2018

Nucleic Acids Research

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The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T–T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)–acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T–T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T–T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT–acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1.

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Myotonic dystrophy: candidate small molecule therapeutics

Cited by 47 publications

References 66 publications

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Skeletal muscle in health and disease

Selective alkylation of T–T mismatched DNA using vinyldiaminotriazine–acridine conjugate

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