Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

Bargiela, Ariadna; Sabater-Arcis, María; Espinosa-Espinosa, Jorge; Zulaica, Miren; Munáin, Adolfo López de; Artero, Rubén

doi:10.1073/pnas.1820297116

Cited by 35 publications

(52 citation statements)

References 53 publications

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“…An antisense oligonucleotide-based reagent, ISIS-DMPK-2.5 RX , was the first potential DM1-specific drug which underwent clinical research [ 304 , 310 ]. However, due to low therapeutic effect in DM1 patients’ tissues the trial was halted whereas new potential reagents are being intensively screened [ 309 , 311 , 312 , 313 ].…”

Section: Splicing-related Diseases Mediated By Rna Structural Arramentioning

confidence: 99%

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Taylor

Sobczak

2020

IJMS

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Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields.

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Section: Splicing-related Diseases Mediated By Rna Structural Arramentioning

confidence: 99%

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Taylor

Sobczak

2020

IJMS

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“…However, at the 40-mg/kg dose, the transcribed levels of Mbnl1 in mouse muscle exceeded 2 to 2.5 times the level of endogenous expression in FVB mice, according to the levels observed in other experiments where the level of expression of Mbnl1 mRNA between HSA LR mice treated with PBS and FVB is similar. 28 Likewise, the 12.5-mg/kg dosage also shows a healthy rescue of Mbnl1 protein levels and distribution, mis-splicing, myotonia, and muscle weakness. These results emphasize that antagomiR-23b can be fine-tuned to an effective and nontoxic concentration.…”

Section: Discussionmentioning

confidence: 94%

“… 24 , 25 , 26 Muscleblind overexpression also rescued muscle atrophy and excessive autophagy levels in an inducible fly model, 27 and autophagy was reduced after treatment with Muscleblind-increasing chloroquine treatment in the same model. 28 MBNL1 upregulation in DM1 mice and patient-derived fibroblasts is well tolerated and rescues several symptoms, such as myotonia and mis-splicing events, as well as the reduction of foci formation. 29 , 30 , 31 Finally, genetic variations in the promoter of MBNL1 have been shown to correlate with disease severity, further implicating MBNL1 in DM1.…”

Section: Introductionmentioning

confidence: 94%

Therapeutic Potential of AntagomiR-23b for Treating Myotonic Dystrophy

Cerro-Herreros

González-Martínez

Moreno-Cervera

et al. 2020

Molecular Therapy - Nucleic Acids

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Myotonic dystrophy type 1 (DM1) is a chronically debilitating, rare genetic disease that originates from an expansion of a noncoding CTG repeat in the dystrophia myotonica protein kinase ( DMPK ) gene. The expansion becomes pathogenic when DMPK transcripts contain 50 or more repetitions due to the sequestration of the muscleblind-like (MBNL) family of proteins. Depletion of MBNLs causes alterations in splicing patterns in transcripts that contribute to clinical symptoms such as myotonia and muscle weakness and wasting. We previously found that microRNA (miR)-23b directly regulates MBNL1 in DM1 myoblasts and mice and that antisense technology (“antagomiRs”) blocking this microRNA (miRNA) boosts MBNL1 protein levels. Here, we show the therapeutic effect over time in response to administration of antagomiR-23b as a treatment in human skeletal actin long repeat (HSA LR ) mice. Subcutaneous administration of antagomiR-23b upregulated the expression of MBNL1 protein and rescued splicing alterations, grip strength, and myotonia in a dose-dependent manner with long-lasting effects. Additionally, the effects of the treatment on grip strength and myotonia were still slightly notable after 45 days. The pharmacokinetic data obtained provide further evidence that miR-23b could be a valid therapeutic target for DM1.

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“…Several candidate therapies have been tested in DM1 models, but none have reached clinical practice yet. Bargiela et al suggested chloroquine as a possible strategy based on the finding that chloroquine treatment is able to upregulate musclebind levels in in vitro and in vivo models [17]. At the beginning of the COVID-19 pandemic, (hydroxy)chloroquine was proposed as one of the most promising drugs due to its anti-viral and immunosuppressive properties.…”

Section: Discussionmentioning

confidence: 99%

Myotonic dystrophy type 1 as a major risk factor for severe COVID-19?

et al. 2020

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The coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide. People with myotonic dystrophy type 1 (DM1) represent a high-risk population during infectious disease outbreaks, little is known about the potential impact of COVID-19 on patients with DM1. We studied the clinical course of COVID-19 in three hospitalized patients with myotonic dystrophy type 1 or Steinert's disease, between April 1, 2020-April 30-2020. All three had advanced Steinert's disease receiving non-invasive nocturnal home ventilatory support. Two of them lived in a residential care centre. Two patients had a limited respiratory capacity, whereas one patient had a rather preserved functional capacity but more comorbidities. Two out of three patients were obese, none of them had diabetes mellitus. Two patients received hydroxychloroquine. Despite maximal supportive care with oxygen therapy, antibiotics, intensive respiratory physiotherapy and noninvasive positive pressure ventilation, all three patients eventually died due to COVID-19. Our case series of three patients with DM1 admitted for COVID-19 confirms that they are at high risk for severe disease and poor outcome. Clinical trials are needed to define best practices and determinants of outcomes in this unique population.

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Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

Cited by 35 publications

References 53 publications

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Therapeutic Potential of AntagomiR-23b for Treating Myotonic Dystrophy

Myotonic dystrophy type 1 as a major risk factor for severe COVID-19?

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