@misc{10481/80893,
year = {2023},
month = {2},
url = {https://hdl.handle.net/10481/80893},
abstract = {Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy,
is caused by an abnormal expansion of CTG repeats in the 30 untranslated region of the dystrophia
myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin
structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing
regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins
result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1
pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1,
rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDAapproved
drug library, we have screened for a reduction of CUG foci in patient muscle cells and
identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/
endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment.
Vorinostat treatment in a mouse model of DM1 (human skeletal actin–long repeat; HSALR) improved
several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at
the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease
markers marks vorinostat as a promising novel DM1 therapy.},
organization = {Genome Canada},
organization = {Canadian Institutes of Health Research (CIHR)	400349},
organization = {Ontario Genomics	OGI-049},
organization = {Children's Hospital of Eastern Ontario (CHEO) Foundation},
publisher = {MDPI},
keywords = {Myotonic dystrophy type 1},
keywords = {Rare diseases},
keywords = {Vorinostat},
keywords = {New treatment},
title = {Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model},
doi = {10.3390/ijms24043794},
author = {Neault, Nafisa and Plaza Díaz, Julio and Abadía Molina, Francisco},
}