Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model

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 3′ 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 FDA-approved 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.

Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases

“…In these frameworks, splicing defects can be overcome by manipulating HDACs. In addition to that, a recent study proved that SAHA is also capable to counteract splicing abnormalities by rescuing RNA foci, as demonstrated in a mouse model of myotonic dystrophy type 1 (DM1) [ 23 ]. DM1 is the most common form of adult neuromuscular dystrophy caused by the abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonic protein kinase ( DMPK ) gene.…”

“…More interestingly, the daily intraperitoneal injections of SAHA in DM1 mice and the daily administration in DM1 patient-derived myoblasts counteract the aberrant splicing affecting myotonia genes (e.g., chloride channel genes) [ 23 ]. Moreover, Nakano et al [ 25 ] proved the efficacy of SAHA to counteract aberrant gene expression caused by the defective splicing of the RE1 silencing transcription factor (REST) gene.…”

“…Indeed, in an RP-rd1 mouse model ablated in the rhodopsin gene whose mutations cause a recessive form of retinitis pigmentosa (RP), SAHA treatments increased the photoreceptor cell survival and improved mitochondrial respiration in the retina [ 62 ]. In a more recent study, SAHA treatments carried out in patient-derived myoblasts with myotonic dystrophy type 1 (DM1) and in a murine DM1 model reduced RNA foci formation and thus restored aberrant splicing [ 23 ]. This capacity of SAHA to counteract the defects caused by aberrant alternative splicing isoforms has also been detected in the mouse model for the autosomal dominant deafness 27 (DFNA27; OMIM 612431), caused by mutations in the REST gene [ 25 ].…”

“…In view of more in-depth studies on the pharmacology response of SAHA, the main point of this review is to highlight the neuroplasticity property of SAHA that could be tested in animal models of neurological disorders that have not been tested to date, giving an overview of cellular and animal models tested, functional processes analyzed, and molecular pathways sensitive to this epi-treatment. In particular, this article aims to review studies on the broad capacity of SAHA in governing neuroplasticity, providing a more complete picture of its multiple activities—at both molecular and cellular levels—such as neuronal maturation, activation of autophagy, microtubule remodeling, and neurospecific splicing modulation ( Figure 2 ) [ 11 , 13 , 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Therefore, we discuss evidence supporting that SAHA-sensitive processes are highly interconnected mechanisms that come together in common neuronal functions.…”

New Pharmacological Approaches for Rare Diseases

“…New ongoing therapeutic approaches for treating specific MDs are also discussed for application in myotonic dystrophy type 1 (DM1), the most common form of adult MD, in Duchenne MD [ 3 ], or in limb-girdle MD R1 calpain 3-related (LGMDR1). These strategies explore different drug discovery approaches, including drug repurposing of the antitumor drug vorinostat for DM1 [ 4 ], the potential of natural products such as ectoine or of biologicals such as BLS-M22 for Duchenne MD [ 5 , 6 ], or the validation of glycogen synthase kinase 3β (GSK-3β) as a new therapeutic target for LGMDR1 [ 7 ]. Emerging therapies for other genetic rare diseases such as inherited peripheral neuropathies, collectively called Charcot–Marie–Tooth disease (CMT), are also covered [ 8 ].…”