Early clinical and pre-clinical therapy development in Nemaline Myopathy.
Fisher G., Mackels L., Markati T., Sarkozy A., Ochala J., Jungbluth H., Ramdas S., Servais L.
INTRODUCTION: : Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently available treatments are supportive. AREAS COVERED: We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimise muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes. EXPERT OPINION: : The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodelling. Challenges to clinical translation include the rarity and heterogeneity of genotypes, phenotypes and disease trajectories, as well as lack of longitudinal natural history data and validated outcomes and biomarkers.