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Current understanding of molecular pathology and treatment of cardiomyopathy in duchenne muscular dystrophy.

ABSTRACT: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of the main causes of death. The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage. Moreover, it pathologically alters intracellular calcium (Ca2+) concentration, neuronal nitric oxide synthase (nNOS) localization and mitochondrial function and leads to inflammation and necrosis, all contributing to the development of cardiomyopathy. Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense. Several preclinical therapies are undergoing development, including utrophin up-regulation, stop codon read-through therapy, viral gene therapy, cell-based therapy and exon skipping. Some of these therapies are undergoing clinical trials, but these have predominantly focused on skeletal muscle correction. However, improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function. This review consolidates what is known regarding molecular pathology of the DMD heart, specifically focusing on intracellular Ca2+, nNOS and mitochondrial dysregulation. It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology, with a focus on the heart.

SUBMITTER: van Westering TL

PROVIDER: S-EPMC6272314 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Current understanding of molecular pathology and treatment of cardiomyopathy in duchenne muscular dystrophy.

van Westering Tirsa L E TL Betts Corinne A CA Wood Matthew J A MJ

Molecules (Basel, Switzerland) 20150515 5

Duchenne muscular dystrophy (DMD) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of the main causes of death. The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage. Moreover, it pathologically alters intracellular calcium (Ca2+) concentration, neuronal ni ...[more]

PMID: 25988613

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Project description:Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying mutations using new gene-editing technologies and corticosteroid analogs with better safety profiles offers renewed hope for many individuals with DMD and their families.

Project description:Congenital muscular dystrophy (CMD) is a class of severe early-onset muscular dystrophies affecting skeletal/cardiac muscles as well as the central nervous system (CNS). Laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2 MD), also known as merosin-deficient congenital muscular dystrophy type 1A (MDC1A), is an autosomal recessive CMD characterized by severe muscle weakness and degeneration apparent at birth or in the first 6 months of life. LAMA2 MD is the most common congenital muscular dystrophy, affecting approximately 4 in 500,000 children. The most common cause of death in early-onset LAMA2 MD is respiratory tract infection, with 30% of them dying within the first decade of life. LAMA2 MD is caused by loss-of-function mutations in the LAMA2 gene encoding for the laminin-α2 chain, one of the subunits of laminin-211. Laminin-211 is an extracellular matrix protein that functions to stabilize the basement membrane and muscle fibers during contraction. Since laminin-α2 is expressed in many tissue types including skeletal muscle, cardiac muscle, Schwann cells, and trophoblasts, patients with LAMA2 MD experience a multi-systemic clinical presentation depending on the extent of laminin-α2 chain deficiency. Cardiac manifestations are typically associated with a complete absence of laminin-α2; however, recent case reports highlight cardiac involvement in partial laminin-α2 chain deficiency. Laminin-211 is also expressed in the brain, and many patients have abnormalities on brain imaging; however, mental retardation and/or seizures are rarely seen. Currently, there is no cure for LAMA2 MD, but various therapies are being investigated in an effort to lessen the severity of LAMA2 MD. For example, antisense oligonucleotide-mediated exon skipping and CRISPR-Cas9 genome editing have efficiently restored the laminin-α2 chain in mouse models in vivo. This review consolidates information on the clinical presentation, genetic basis, pathology, and current treatment approaches for LAMA2 MD.

Dataset Information

Current understanding of molecular pathology and treatment of cardiomyopathy in duchenne muscular dystrophy.

Publications

Current understanding of molecular pathology and treatment of cardiomyopathy in duchenne muscular dystrophy.

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