Myotonic dystrophy type 1 drug development: A pipeline toward the market

Pascual-Gilabert, Marta; López-Castel, Arturo; Artero, Rubén

doi:10.1016/j.drudis.2021.03.024

Cited by 43 publications

(33 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Current treatment approaches for cardiac disease in DM1 fall within standard paradigms of cardiology practice. A number of approaches are being investigated to treat DM1, including small molecules, gene therapy, antisense oligonucleotides (ASOs), CRISPR/Cas9 mediated deletion of (CTG) repeats, and cell-based therapies [ 132 ]. Many companies are developing ASO based approaches to treat DM1.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Pathology in Myotonic Dystrophy Type 1

Mahadevan

Yadava

Mandal

2021

IJMS

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

show abstract

Section: Discussionmentioning

confidence: 99%

Cardiac Pathology in Myotonic Dystrophy Type 1

Mahadevan

Yadava

Mandal

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Functionally, these structural alterations lead to abnormal nerve conduction and pathological jitter in DM1 patients ( Bombelli et al, 2016 ). Currently there are no curative therapeutics for either DM1 or DM2 ( Pascual-Gilabert et al, 2021 ). However, nearly two dozen preclinical and clinical drug development programs are currently active encompassing repurposed drugs, gene therapy, oligonucleotide therapeutics, and novel chemical treatments ( Pascual-Gilabert et al, 2021 ).…”

Section: Neuromuscular Diseasesmentioning

confidence: 99%

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

Fralish

Lotz

Chavez

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.

show abstract

“…A Phase II clinical trial on adult patients with DM1 is currently underway to investigate the clinical effects of erythromycin after oral administration ( Jenquin et al, 2019 ). Other molecules evaluated in clinical trials for specific disease symptoms (e.g., insulin resistance phenotype, myotonia, myalgia, or daytime sleepiness) include metformin, mexiletine, ranolazine, cannabinoids, pitolisant, Caffeine, and theobromine formulation MYODM TM ( Kouki et al, 2005 ; Logigian et al, 2010 ; Laustriat et al, 2015 ; Bassez et al, 2018 ; Vita et al, 2019 ; Heatwole et al, 2021 ; reviewed in Pascual-Gilabert et al, 2021 ).…”

Section: Therapeutic Strategies Of Dm1mentioning

confidence: 99%

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

Liu

Guo

Yan

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy that affects multiple systems including the muscle and heart. The mutant CTG expansion at the 3′-UTR of the DMPK gene causes the expression of toxic RNA that aggregate as nuclear foci. The foci then interfere with RNA-binding proteins, affecting hundreds of mis-spliced effector genes, leading to aberrant alternative splicing and loss of effector gene product functions, ultimately resulting in systemic disorders. In recent years, increasing clinical, imaging, and pathological evidence have indicated that DM1, though to a lesser extent, could also be recognized as true brain diseases, with more and more researchers dedicating to develop novel therapeutic tools dealing with it. In this review, we summarize the current advances in the pathogenesis and pathology of central nervous system (CNS) deficits in DM1, intervention measures currently being investigated are also highlighted, aiming to promote novel and cutting-edge therapeutic investigations.

show abstract

Myotonic dystrophy type 1 drug development: A pipeline toward the market

Cited by 43 publications

References 61 publications

Cardiac Pathology in Myotonic Dystrophy Type 1

Cardiac Pathology in Myotonic Dystrophy Type 1

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

Contact Info

Product

Resources

About