TY - JOUR

T1 - Early clinical and pre-clinical therapy development in Nemaline myopathy

AU - Fisher, Gemma

AU - Mackels, Laurane

AU - Markati, Theodora

AU - Sarkozy, Anna

AU - Ochala, Julien

AU - Jungbluth, Heinz

AU - Ramdas, Sithara

AU - Servais, Laurent

PY - 2022/12/28

Y1 - 2022/12/28

N2 - IntroductionNemaline 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 coveredWe 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 optimize 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 OpinionThe 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 remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.

AB - IntroductionNemaline 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 coveredWe 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 optimize 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 OpinionThe 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 remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.

KW - Congenital myopathy

KW - NEB

KW - ACTA1

KW - gene therapy

KW - exon skipping

KW - myostatin

KW - fast troponin activators

KW - pyridostigmine

KW - SKELETAL-MUSCLE TROPONIN

KW - CONGENITAL MYOPATHIES

KW - NEUROMUSCULAR-TRANSMISSION

KW - PROTEIN-KINASE

KW - GENE-THERAPY

KW - NEBULIN GENE

KW - MUTATION

KW - GROWTH

KW - PHENOTYPE

KW - ACTIVATION

U2 - 10.1080/14728222.2022.2157258

DO - 10.1080/14728222.2022.2157258

M3 - Review

C2 - 36524401

VL - 26

SP - 853

EP - 867

JO - Expert Opinion on Therapeutic Targets

JF - Expert Opinion on Therapeutic Targets

SN - 1472-8222

IS - 10

ER -