Moving neuromuscular disorders research forward: from novel models to clinical studies

Abstract

Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field.

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

“…We believe that preclinical investigations could benefit also from a preliminary phenotypic in vitro screening based upon the findings here reported, i.e., upon the ability of candidate SOCE/CRAC inhibitors to counteract the differentiation alterations associated with Ca 2+ overload. As it is usually desired for neuromusculuar disorders (Silva-Rojas et al, 2020;van Putten et al, 2020), a such experimental approach could finally allow a reliable translation in the clinical management of TAM patients.…”

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

“…In this case, exon-skipping of damaged dystrophin in DMD generates a shortened but still functional version of dystrophin [ 154 ]. Other NMDs like LGMD could benefit from ASO exon skipping, by restoring the disrupted reading frame of the SGCG gene [ 5 , 27 ].…”

“…Given the rarity and diversity of NMDs, patients experience long delays in diagnosis (typically 7 years) and 30% are never achieved [ 1 ], probably because many of them lack non-invasive diagnostic and prognostic biomarkers. Likewise, models of disease or therapeutic options are infrequent, but growing interests and knowledge are focused in depicting the etiology of these disorders [ 5 ].…”

Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases

“…Effective treatment options are not available for the majority of NMD cases due to their rarity and unique characteristics, complicated genetic pathophysiology and large portion of the affected area in the body 32. However, successful treatment strategies, such as antisense gene therapy in DMD, have recently been introduced in clinical practice.…”