Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics

Timchenko, Lubov

doi:10.3390/ijms231911954

Cited by 2 publications

(2 citation statements)

References 20 publications

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“…The Protein Kinase C (PKC) inhibitors-Ro-31-8220 and hypericin had been shown in our previous study to remove nuclear foci, affect MBNL distribution and influence CELF-1 protein levels by PKC-independent mechanism in DM cells (24). Currently, there is ongoing work to search for small molecules for DM therapy (Timchenko, 2022). Therefore, the cell-based double reporter gene splicing assay developed and applied to small molecules screening test in this study is a good model assay system for therapeutic screening for myotonic dystrophy.…”

Section: Discussion Discussionmentioning

confidence: 99%

A Cell-Based Double Reporter Gene Splicing Assay for Therapeutic Screening in Myotonic Dystrophy

Udosen

Granados

Brook

2023

The EuroBiotech Journal

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The study has developed a model splicing construct assay system based on splicing misregulation, one of the major molecular features associated with myotonic dystrophy. The splicing construct assay has double reporters for intron 2 splicing in chloride channel (CLCN1). The CLCN1 transgene splicing construct assay was used to transfect wild type and DM fibroblast cell lines and the clones generated showed that it enabled quantification of splicing efficiency in transgene construct. Validation of the DM fibroblasts containing transgene splicing construct was performed by differentiating the DM fibroblasts into myoblasts which exhibited a switch in CLCN1 splicing construct which was consistent with that associated with myotonic dystrophy (DM) condition. The myoblast derived from fibroblasts cell-based gene-splicing assay was subsequently applied in therapeutic screening in small throughput screens of 113 compounds which identified Protein Kinase C inhibitors- hypericin and Ro-31-8220 as potential therapeutic agents. The CLCN1 gene-splicing assay is a good model system for application in therapeutic screening in myotonic dystrophy because its double reporters facilitated quantification of effect putative drug on correction of misregulated splicing.

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Section: Discussion Discussionmentioning

confidence: 99%

A Cell-Based Double Reporter Gene Splicing Assay for Therapeutic Screening in Myotonic Dystrophy

Udosen

Granados

Brook

2023

The EuroBiotech Journal

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“…Regarding individual DM1 manifestations, the n(CTG) in leukocytes directly correlates also with the global muscle disease severity [4], and it is associated with the development of restrictive respiratory syndrome [6], and severe cardiac conduction defects [7]. Results regarding the correlation between the n(CTG) expansion in leukocytes and other DM1 manifestations are controversial, likely because of somatic tissue mosaicism and the limited size of the cohorts assessed in different studies [8].…”

Section: Introductionmentioning

confidence: 99%

Fluid Biomarkers of Central Nervous System (CNS) Involvement in Myotonic Dystrophy Type 1 (DM1)

Rossi

Silvestri

2023

IJMS

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Myotonic dystrophy type 1 (DM1), commonly known as Steinert’s disease (OMIM #160900), is the most common muscular dystrophy among adults, caused by an unstable expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of DMPK. Besides skeletal muscle, central nervous system (CNS) involvement is one of the core manifestations of DM1, whose relevant cognitive, behavioral, and affective symptoms deeply affect quality of life of DM1 patients, and that, together with muscle and heart, may profoundly influence the global disease burden and overall prognosis. Therefore, CNS should be also included among the main targets for future therapeutic developments in DM1, and, in this regard, identifying a cost-effective, easily accessible, and sensitive diagnostic and monitoring biomarker of CNS involvement in DM1 represents a relevant issue to be addressed. In this mini review, we will discuss all the papers so far published exploring the usefulness of both cerebrospinal fluid (CSF) and blood-based biomarkers of CNS involvement in DM1. Globally, the results of these studies are quite consistent on the value of CSF and blood Neurofilament Light Chain (NfL) as a biomarker of CNS involvement, with less robust results regarding levels of tau protein or amyloid-beta.

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Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics

Abstract: Current studies concerning myotonic dystrophy type 1 (DM1) are in the process of transitioning from molecular investigations to preclinical and clinical trials [...]

Cited by 2 publications

References 20 publications

A Cell-Based Double Reporter Gene Splicing Assay for Therapeutic Screening in Myotonic Dystrophy

A Cell-Based Double Reporter Gene Splicing Assay for Therapeutic Screening in Myotonic Dystrophy

Fluid Biomarkers of Central Nervous System (CNS) Involvement in Myotonic Dystrophy Type 1 (DM1)

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