scholarly journals Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Caroline Le Guiner ◽  
Laurent Servais ◽  
Marie Montus ◽  
Thibaut Larcher ◽  
Bodvaël Fraysse ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Canine Model

Duchenne muscular dystrophy gene therapy in the canine model

2018 ◽  
Author(s):  
◽  
Kasun Kodippili
Keyword(s):  
Skeletal Muscle ◽  
Gene Therapy ◽  
Animal Model ◽  
Duchenne Muscular Dystrophy ◽  
Sarcoplasmic Reticulum ◽  
Muscular Dystrophy ◽  
Canine Model ◽  
Disease Pathogenesis ◽  
Preclinical Treatment ◽  
Expression And Activity

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by loss of function mutations in the dystrophin gene, resulting in the absence of dystrophin, a structural protein in muscle. DMD is the most common form of inherited muscle disease in childhood, with an incidence of 1 in 5000 live male births worldwide. The dystrophin-null mdx mouse has been the most widely used animal model for DMD research over the last 30 years. Dystrophin-deficient DMD dogs have also gained prominence as a highly relevant preclinical animal model due to their high phenotypic homology to human DMD patients. Preclinical treatment studies in these dogs are expected to better inform and guide clinical trials in human patients. However, there are still significant gaps in our understanding of the disease pathogenesis and gene therapy in the canine model. The goals of my dissertation work were to establish reagents and methodologies to study preclinical treatment in the canine model, and subsequently characterize the disease pathogenesis and gene therapy in DMD dogs. To this end, I first characterized 65 epitope-specific human dystrophin monoclonal antibodies for their reactivity in canine skeletal and cardiac muscle by both immunofluorescence (IF) staining and western blot. I found species-specific, tissue-specific and assay-specific patterns of reactivity in these antibodies. Importantly, out of the 65 antibodies that I characterized, I recognized 15 antibodies that worked well for canine tissue on both IF staining and western blot, which are recommended for DMD research in the canine model. ... Dystrophin-independent gene therapy for DMD takes advantage of disease-modifying genes that are either structural and/or functional homologues of dystrophin, or alternative targets that are involved in disease pathogenesis. One such alternative target gene is the sarcoplasmic reticulum calcium ATPase 2a (SERCA2a), a pump that transports calcium ions from the cytoplasm into the sarcoplasmic reticulum. I show that SERCA2a expression and activity are impaired, and that calcium homeostasis is dysregulated in DMD dog skeletal muscle. Furthermore, gene therapy with human SERCA2a restored expression and activity of the pump, and improved several aspects of muscle function and histopathology in DMD dog skeletal muscle. In summary, this dissertation work advances our knowledge of the disease pathogenesis and gene therapy prospects in the canine model of DMD, a highly relevant and valuable preclinical DMD model.

scholarly journals Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence

2022 ◽  
Vol 12 ◽  
Author(s):  
Arianna Manini ◽  
Elena Abati ◽  
Andi Nuredini ◽  
Stefania Corti ◽  
Giacomo Pietro Comi
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Genetic Material ◽  
Premature Death ◽  
Gene Replacement ◽  
Neuromuscular Disorder ◽  
Adeno Associated Virus ◽  
Dmd Gene

Duchenne muscular dystrophy (DMD) is an X-linked recessive, infancy-onset neuromuscular disorder characterized by progressive muscle weakness and atrophy, leading to delay of motor milestones, loss of autonomous ambulation, respiratory failure, cardiomyopathy, and premature death. DMD originates from mutations in the DMD gene that result in a complete absence of dystrophin. Dystrophin is a cytoskeletal protein which belongs to the dystrophin-associated protein complex, involved in cellular signaling and myofiber membrane stabilization. To date, the few available therapeutic options are aimed at lessening disease progression, but persistent loss of muscle tissue and function and premature death are unavoidable. In this scenario, one of the most promising therapeutic strategies for DMD is represented by adeno-associated virus (AAV)-mediated gene therapy. DMD gene therapy relies on the administration of exogenous micro-dystrophin, a miniature version of the dystrophin gene lacking unnecessary domains and encoding a truncated, but functional, dystrophin protein. Limited transgene persistence represents one of the most significant issues that jeopardize the translatability of DMD gene replacement strategies from the bench to the bedside. Here, we critically review preclinical and clinical studies of AAV-mediated gene therapy in DMD, focusing on long-term transgene persistence in transduced tissues, which can deeply affect effectiveness and sustainability of gene replacement in DMD. We also discuss the role played by the overactivation of the immune host system in limiting long-term expression of genetic material. In this perspective, further studies aimed at better elucidating the need for immune suppression in AAV-treated subjects are warranted in order to allow for life-long therapy in DMD patients.

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