Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the laminin-α2 gene (OMIM: 607855). Currently, no treatment other than palliative care exists for this disease. In our previous work, genetic interventions in the Lama2(Dy-w) mouse model for MDC1A demonstrated that limited regeneration and uncontrolled apoptosis are important drivers of this disease. However, targeting one of these disease drivers without addressing the other results in only partial rescue of the phenotype. The present study was designed to determine whether utilizing a combinatorial treatment approach can lead to a more profound amelioration of the disease pathology. To accomplish this task, we generated Bax-null Lama2(Dy-w)mice that overexpressed muscle-specific IGF-1 (Lama2(Dy-w)Bax(-/-)+IGF-1tg). Further to test the translational potential of IGF-1 administration in combination with Bax inhibition, we treated Lama2(Dy-w)Bax(-/-) mice postnatally with systemic recombinant human IGF-1 (IPLEX™). These two combinatorial treatments lead to similar, promising outcomes. In addition to increased body and muscle weights, both transgenic overexpression and systemic administration of IGF-1 combined with Bax-inhibition resulted in improved muscle phenotype and locomotory function that were nearly indistinguishable from wild-type mice. These results provide a fundamental proof of concept that justifies the use of a combination therapy as an effective treatment for MDC1A and highlights a compelling argument toward shifting the paradigm in treating multifaceted neuromuscular diseases.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1093/hmg/ddt280 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Favorable response to ketogenic diet therapy in a patient with -related epilepsy.
Epilepsy Behav Rep
March 2025
Section of Pediatric Neurology, Department of Pediatrics, The University of Chicago, Chicago, IL, United States.
Dynein Cytoplasmic 1 Heavy chain 1 (-related disorders are a spectrum of conditions including neurodevelopmental disorders, congenital brain malformations, and neuromuscular diseases. These clinical features may co-occur, with four main disease entities including epilepsy with developmental epileptic encephalopathy such as infantile epileptic spasms syndrome (IESS) and Lennox-Gastaut syndrome (LGS), axonal Charcot-Marie-Tooth disease type 2O, spinal muscular atrophy with lower extremity-predominance (SMALED), and congenital cortical malformations. Epilepsy associated with this disorder often becomes drug-resistant and requires multiple medications and, in some cases, non-pharmacological treatments.
View Article and Find Full Text PDFMidterm Outcomes of Endovascular Pulmonary Artery Debanding in Children.
Catheter Cardiovasc Interv
January 2025
Department of Pediatric Cardiology, Hotel Dieu de France University Medical Center, Saint Joseph University, Beirut, Lebanon.
Background: Pulmonary artery banding (PAB) palliates pulmonary over-circulation, while endovascular debanding (ED) offers a less invasive alternative to repeat surgery.
Objectives: To evaluate our experience with ED.
Aims: Retrospective review of single-center data (2015-2023) on children with single, multiple, or "Swiss-cheese" muscular ventricular septal defects (MVSDs) undergoing ED.
Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasias.
Pediatr Radiol
January 2025
Department of Pediatric Genetics, Istanbul University-Cerrahpaşa, Cerrahpasa Medical Faculty, 34098, Cerrahpasa, Istanbul, Turkey.
Background: Heterozygous TRPV4 mutations cause a group of skeletal dysplasias characterized by short stature, short trunk, and skeletal deformities.
Objective: The aim of this study is to compare the natural history of clinical and radiologic features of patients with different TRPV4-related skeletal dysplasias.
Materials And Methods: Thirteen patients with a mutation in TRPV4 were included in the study, and 11 were followed for a median of 6.
Successful Diagnosis of Sengers Syndrome Using a Comprehensive Genomic Analysis.
Mol Genet Genomic Med
January 2025
Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Background: Sengers syndrome is an autosomal recessive mitochondrial DNA depletion syndrome characterized by hypertrophic cardiomyopathy, congenital cataracts, skeletal myopathy, exercise intolerance, and lactic acidosis. Dysfunction of acylglycerol kinase (AGK) is responsible for the disease, and several AGK gene variants have been reported.
Methods: We employed a comprehensive genomic analysis approach, including whole-genome sequencing and RNA sequencing, combined with various bioinformatics tools.
Congenital muscular dystrophies and myopathies: the leading cause of genetic muscular disorders in eleven Chinese families.
BMC Musculoskelet Disord
January 2025
Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, 18 Daoshan Road, Fuzhou, 350001, China.
Background: Congenital muscular dystrophies (CMDs) and myopathies (CMYOs) are a clinically and genetically heterogeneous group of neuromuscular disorders that share common features, such as muscle weakness, hypotonia, characteristic changes on muscle biopsy and motor retardation. In this study, we recruited eleven families with early-onset neuromuscular disorders in China, aimed to clarify the underlying genetic etiology.
Methods: Essential clinical tests, such as biomedical examination, electromyography and muscle biopsy, were applied to evaluate patient phenotypes.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!