Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening

Jenquin, Jana R.; O’Brien, Alana; Poukalov, Kiril; Lu, Yidan; Frías, Jesús; Shorrock, Hannah K.; Richardson, Jared; Mazdiyasni, Hormoz; Yang, Hongfen; Huigens, Robert W.; Boykin, David W.; Ranum, Laura P.W.; Cleary, John D.; Wang, Eric T.; Berglund, J. Andrew

doi:10.1016/j.isci.2022.104198

Cited by 8 publications

(13 citation statements)

References 53 publications

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“…A search for the drugs that reduce MBNL1 binding to CCUG repeats by the screening of the compound libraries identified various small molecules that could reduce the number of CCUG foci and correct mis-splicing associated with MBNL1 sequestration in DM2 cells [ 59 , 90 , 91 , 92 , 93 , 94 , 95 ]. These compounds were tested in pre-clinical studies mainly in DM2 cell lines and in the mutant CCUG-expressing flies addressing their effects on the splicing of the MBNL1 targets and reduction in CCUG foci.…”

Section: Therapeutic Studies In Dm2mentioning

confidence: 99%

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Timchenko

2022

IJMS

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Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients’ cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

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Section: Therapeutic Studies In Dm2mentioning

confidence: 99%

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Timchenko

2022

IJMS

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“…Treatment of unaffected control myotubes performed in parallel did not reveal changes to the splicing profile of the same events nor did treatment of DM1 myotubes reveal changes to previously identified (22) non-DM1 associated alternative splicing events (fig. S5, S6).…”

Section: Validation Of Quercetin Activity In Dm1 Patient-derived Myot...mentioning

confidence: 82%

“…S2B). Based on the shared mechanism of toxic RNA pathogenesis in DM1 and DM2, we also tested the effect of quercetin treatment in characterized DM2 patient derived fibroblasts ( 22 ) using the same mis-splicing events (fig. S3A).…”

Section: Resultsmentioning

confidence: 99%

“…Selective reduction of expanded CUG/CCUG RNA by quercetin does not appear to be affected by the length of the CTG/CCTG repeats. The CTG and CCTG repeats tested in the cell lines and HSA LR mouse model ranged from ~220 CTG repeats in the HSA LR mouse model (27) to ~2,900 CTG repeats in DM1 myotubes (26) and ~3000 CCTG repeats in DM2 fibroblasts (22).…”

Section: Discussionmentioning

confidence: 99%

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Quercetin selectively reduces expanded repeat RNA levels in models of myotonic dystrophy

Mishra

Hicks

Frías

et al. 2023

Preprint

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Myotonic dystrophy is a multisystemic neuromuscular disease caused by either a CTG repeat expansion in DMPK (DM1) or a CCTG repeat expansion in CNBP (DM2). Transcription of the expanded alleles produces toxic gain-of-function RNA that sequester the MBNL family of alternative splicing regulators into ribonuclear foci, leading to pathogenic mis-splicing. There are currently no approved treatments that target the root cause of disease which is the production of the toxic expansion RNA molecules. In this study, using our previously established HeLa DM1 repeat selective screening platform, we identified the natural product quercetin as a selective modulator of toxic RNA levels. Quercetin treatment selectively reduced toxic RNA levels and rescued MBNL dependent mis-splicing in DM1 and DM2 patient derived cell lines and in the HSALR transgenic DM1 mouse model where rescue of myotonia was also observed. Based on our data and its safety profile for use in humans, we have identified quercetin as a priority disease-targeting therapeutic lead for clinical evaluation for the treatment of DM1 and DM2.

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“… 21 , 22 Moreover, the length of CCUG exp may be also deeply heterogeneous in the same patient, as indicated by recent studies showing variability in repeat length and repeat composition. 23 , 24 Hence, the sequestration of MBNL proteins is highly heterogeneous in both DM forms, even in the same tissue of the same patient.…”

Section: Introductionmentioning

confidence: 99%

Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy

Rogalska¹,

Sobczak²

2022

Molecular Therapy - Nucleic Acids

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Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening

Cited by 8 publications

References 53 publications

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Quercetin selectively reduces expanded repeat RNA levels in models of myotonic dystrophy

Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy

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