scholarly journals Gene Therapy for Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Nertiyan Elangkovan ◽  
George Dickson
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Transfer ◽  
Viral Vector ◽  
Cardiac Complications ◽  
Muscle Fibres ◽  
Large Animal ◽  
Large Animal Models ◽  
Advanced Therapy

Duchenne muscular dystrophy (DMD) is an X-linked, muscle wasting disease that affects 1 in 5000 males. Affected individuals become wheelchair bound by the age of twelve and eventually die in their third decade due to respiratory and cardiac complications. The disease is caused by mutations in the DMD gene that codes for dystrophin. Dystrophin is a structural protein that maintains the integrity of muscle fibres and protects them from contraction-induced damage. The absence of dystrophin compromises the stability and function of the muscle fibres, eventually leading to muscle degeneration. So far, there is no effective treatment for deteriorating muscle function in DMD patients. A promising approach for treating this life-threatening disease is gene transfer to restore dystrophin expression using a safe, non-pathogenic viral vector called adeno-associated viral (AAV) vector. Whilst microdystrophin gene transfer using AAV vectors shows extremely impressive therapeutic success so far in large animal models of DMD, translating this advanced therapy medicinal product from bench to bedside still offers scope for many optimization steps. In this paper, the authors review the current progress of AAV-microdystrophin gene therapy for DMD and other treatment strategies that may apply to a subset of DMD patients depending on the mutations they carry.

Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy

2002 ◽  
Vol 4 (23) ◽  
pp. 1-23 ◽  
Author(s):  
Dominic J. Wells ◽  
Aurora Ferrer ◽  
Kim E. Wells
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Transfer ◽  
Immune Responses ◽  
Muscle Fibres ◽  
Dystrophic Muscle ◽  
Western Blots ◽  
Muscle Wasting Disease

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this ‘neoantigen’. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

scholarly journals Changes in Myonuclear Number During Postnatal Growth –Implications for AAV Gene Therapy for Muscular Dystrophy

2021 ◽  
pp. 1-8
Author(s):  
Jennifer Morgan ◽  
Francesco Muntoni
Keyword(s):  
Skeletal Muscle ◽  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Growth ◽  
Postnatal Growth ◽  
Muscle Fibres ◽  
Postnatal Life ◽  
Adult Skeletal Muscle ◽  
Dividing Cells

Adult skeletal muscle is a relatively stable tissue, as the multinucleated muscle fibres contain post-mitotic myonuclei. During early postnatal life, muscle growth occurs by the addition of skeletal muscle stem cells (satellite cells) or their progeny to growing muscle fibres. In Duchenne muscular dystrophy, which we shall use as an example of muscular dystrophies, the muscle fibres lack dystrophin and undergo necrosis. Satellite-cell mediated regeneration occurs, to repair and replace the necrotic muscle fibres, but as the regenerated muscle fibres still lack dystrophin, they undergo further cycles of degeneration and regeneration. AAV gene therapy is a promising approach for treating Duchenne muscular dystrophy. But for a single dose of, for example, AAV coding for dystrophin, to be effective, the treated myonuclei must persist, produce sufficient dystrophin and a sufficient number of nuclei must be targeted. This latter point is crucial as AAV vector remains episomal and does not replicate in dividing cells. Here, we describe and compare the growth of skeletal muscle in rodents and in humans and discuss the evidence that myofibre necrosis and regeneration leads to the loss of viral genomes within skeletal muscle. In addition, muscle growth is expected to lead to the dilution of the transduced nuclei especially in case of very early intervention, but it is not clear if growth could result in insufficient dystrophin to prevent muscle fibre breakdown. This should be the focus of future studies.

scholarly journals A scalable, clinically severe pig model for Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Michael Stirm ◽  
Lina Marie Fonteyne ◽  
Bachuki Shashikadze ◽  
Magdalena Lindner ◽  
Maila Chirivi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Connexin 43 ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Diagnostic Procedures ◽  
Left Ventricular ◽  
Large Animal ◽  
Large Animal Models ◽  
Disease Mechanisms

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for preclinical evaluation of novel diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but cannot be propagated by breeding due to death before sexual maturity. Therefore, female DMD+/- carriers were generated. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type (WT) offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. The majority of them survived for 3-4 months, providing large cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive fibrosis of myocardium and increased expression of connexin-43, associated with significantly reduced left ventricular fractional shortening and ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability of DMDY/- pigs. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories from DMDY/- pigs, DMD+/- carriers, and WT littermate controls provide important resources for studying DMD disease mechanisms and for testing novel diagnostic procedures and treatment strategies.

scholarly journals Gene Therapy in Large Animal Models of Muscular Dystrophy

ILAR Journal ◽  
2009 ◽  
Vol 50 (2) ◽  
pp. 187-198 ◽  
Author(s):  
Z. Wang ◽  
J. S. Chamberlain ◽  
S. J. Tapscott ◽  
R. Storb
Keyword(s):  
Gene Therapy ◽  
Muscular Dystrophy ◽  
Animal Models ◽  
Large Animal ◽  
Large Animal Models

scholarly journals Longitudinal assessment of blood-borne musculoskeletal disease biomarkers in the DE50-MD dog model of Duchenne muscular dystrophy

2021 ◽  
Vol 6 ◽  
pp. 354
Author(s):  
Dominique O. Riddell ◽  
John C. W. Hildyard ◽  
Rachel C. M. Harron ◽  
Dominic J. Wells ◽  
Richard J. Piercy
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Sample Size ◽  
Venous Blood ◽  
Musculoskeletal Disease ◽  
Large Animal ◽  
Longitudinal Assessment ◽  
Large Animal Models ◽  
Sample Size Calculations

Background: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene. Due to their phenotypic similarity to human patients, large animal models are invaluable tools for pre-clinical trials. The DE50-MD dog is a relatively new model of DMD, and carries a therapeutically-tractable mutation lying within the hotspot for human patients, making it especially valuable. Prior to conducting therapeutic trials using this novel animal model, it is essential to establish a panel of viable biomarkers. Methods: We evaluated a panel of blood-borne biomarkers of musculoskeletal disease in the DE50-MD dog. Venous blood samples were obtained monthly throughout an 18-month study period in DE50-MD (N=18) and wild-type (WT) control (N=14) dogs. A panel of potential plasma/serum biomarkers of DMD was measured and their theoretical utility in future clinical trials determined using sample size calculations. Results: Compared to WT dogs, DE50-MD dogs had substantially higher circulating creatine kinase (CK) activities, myomesin-3 (MYOM3), and the dystromiRs miR-1, miR-133a and miR-206, but significantly lower serum myostatin concentrations. An age-associated pattern, similar to that observed in DMD patients, was seen for CK and MYOM3. Sample size calculations suggested that low cohort sizes (N≤3) could be used to detect up to a 50% improvement in DE50-MD results towards WT levels for each biomarker or a combination thereof (via principal component analysis); as few as N=3 animals should enable detection of a 25% improvement using a combined biomarker approach (alpha 0.05, power 0.8). Conclusions: We have established a panel of blood-borne biomarkers that could be used to monitor musculoskeletal disease or response to a therapeutic intervention in the DE50-MD dog using low numbers of animals. The blood biomarker profile closely mimics that of DMD patients, supporting the hypothesis that this DMD model would be suitable for use in pre-clinical trials.

scholarly journals Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Vratko Himič ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Structural Integrity ◽  
Viral Vector ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Pharmacological Treatments ◽  
Genetic Sequencing ◽  
Reading Frame ◽  
Target Effects

AbstractDuchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

scholarly journals Myostatin Is a Quantifiable Biomarker for Monitoring Pharmaco-gene Therapy in Duchenne Muscular Dystrophy

2020 ◽  
Vol 18 ◽  
pp. 415-421 ◽  
Author(s):  
Virginie Mariot ◽  
Caroline Le Guiner ◽  
Inès Barthélémy ◽  
Marie Montus ◽  
Stéphane Blot ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy
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