2026-07-02 | Muscle-Specific Kinase Signaling and Its Therapeutic Potential.
The function of the neuromuscular junction (NMJ) is compromised in many neuromuscular diseases (NMDs) such as autoimmune or congenital myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies. The NMJ contains muscle-specific kinase (MuSK), which is a critical regulator of NMJ integrity and function. Activating the MuSK signaling cascade may have therapeutic potential in several of these NMDs that are characterized by impaired neuromuscular communication. The MuSK signaling cascade consists of different components and can be activated with interventions at different levels. In the past years, different therapeutic strategies using an engineered recombinant agrin comprised of the C-terminal fragment of the protein (mini-agrin), gene therapy of key proteins in this pathway, agonist MuSK antibodies, and SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitors have been further developed for this purpose. Each of these strategies engages distinct signaling components: mini-agrin, both as recombinant protein and gene therapy, enhances agrin-Lrp4-MuSK interaction; Dok7 gene therapy amplifies MuSK phosphorylation; Lrp4 gene therapy enhances agrin responsiveness; MuSK agonist antibodies bypass upstream defects and promote downstream signaling; SHP2 inhibitors prolong the duration of active MuSK signaling. These therapeutic strategies have ameliorated NMJ integrity and function in several preclinical models of MG, motor neuron diseases, and muscular dystrophies. In this review, we highlight MuSK signaling as a possible therapeutic target, describe the therapeutic efficacy of intervention in MuSK signaling in different NMDs, and present an outlook on future clinical development.
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2026-06-15 | The Effect of Trunk Brace Use on Motor and Pulmonary Functions in a Patient with LAMA2-Related Congenital Muscular Dystrophy: A Case Report.
LAMA2-related congenital muscular dystrophy (CMD), the most common form of CMD, is characterized by very early-onset muscle weakness, trunk instability, neuromuscular scoliosis, and progressive respiratory failure. The effectiveness of trunk bracing in neuromuscular scoliosis is controversial. The aim of this study was to investigate the effects of trunk bracing on spinal alignment, motor function, and pulmonary parameters in a patient diagnosed with LAMA2-related CMD. A 6-year-old female patient with a homozygous LAMA2 deletion and 37° left thoracolumbar scoliosis was recommended to use a thoracolumbar-sacral orthosis (TLSO) while sitting. Assessments were performed at baseline, on day 20, and at week 6. Spinal asymmetry during sitting, Motor Function Measure (MFM), Expanded Hammersmith Functional Motor Scale (HFMSE), Trunk Control Measurement Scale (TCMS), and spirometry-based respiratory function tests (Forced Expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC) were evaluated. The patient continued with a standard physical therapy program twice a week. The average daily corset usage time was 4 hours. The MFM score increased from 27 to 42 points, and the HFMSE score increased from 5 to 9 points. An increase was observed in pulmonary parameters (FEV1: 39-54%; FVC: 40-64%). TCMS scores remained stable (7-7-7 points). No side effects were reported. The use of a trunk brace may have positive effects on sitting posture, motor performance, and pulmonary function in LAMA2-related congenital muscular dystrophy.
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2026-06-15 | Preclinical efficacy of a gene therapy for CHKB-mediated muscular dystrophy.
Loss-of-function variants of the CHKB gene cause an autosomal recessive disease described as an early onset congenital megaconial (large peripheral mitochondria) muscular dystrophy. CHKB encodes choline kinase β, the first enzyme in the biochemical pathway for synthesis of the major membrane phospholipid phosphatidylcholine. Chkb -/- mice recapitulate the human disease with affected skeletal muscle displaying a decrease in strength, myofiber atrophy, megaconial mitochondria, fat accumulation within muscle cells, and an increase in muscle injury. Here, we assessed the therapeutic potential of an AAV therapy for the treatment of CHKB-mediated muscular dystrophy. Chkb -/- mice were injected once suborbitally with three different doses of recombinant AAV9 (rAAV9) encoding human CHKB under control of a constitutive and ubiquitous promoter (AAV9-CHKB). The AAV9-CHKB-treated mice were biochemically and phenotypically indistinguishable from the wild type mice. In the Chkb -/- mouse model, all doses resulted in expression of the CHKB protein and restored choline kinase β enzyme activity, body and muscle weight, and normal muscle cell physiology, and they prevented lipid metabolism imbalance and increased the capacity to walk. These findings point to AAV9-mediated gene therapy as a potential treatment for CHKB-mediated disease.
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