The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs

Cooper, Barry; Winand, Nena J.; Stedman, Hansell H.; Valentine, Beth A.; Hoffman, Eric P.; Kunkel, Louis M.; Scott, Marion-Oronzi; Fischbeck, Kenneth H.; Kornegay, Joe N.; Avery, R. J.; Williams, James R.; Schmickel, Roy D.; Sylvester, James E.

doi:10.1038/334154a0

Cited by 378 publications

(223 citation statements)

References 17 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…This large animal model of DMD offers a number of advantages that are not available to the mdx mice. 10,11 Besides muscle histopathology, the GRMD dogs exhibit clinical signs closely mimicking those observed in humans, for example, muscle atrophy, contractures, overt cardiomyopathy, premature death, and so on. More importantly, the dogs also have a much larger body mass than the mice, making the dogs more relevant to human DMD patients when assessing therapeutic doses of AAV vectors.…”

Section: Introductionmentioning

confidence: 94%

A canine minidystrophin is functional and therapeutic in mdx mice

Wang

Qiao

et al. 2008

Gene Ther

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder lacking a curative treatment. We wish to use the dystrophin-deficient golden retriever muscular dystrophy (GRMD) dog, a canine model of DMD, to investigate adeno-associated virus (AAV) vectormediated minidystrophin gene therapy. The dog model is useful in evaluating vector dose requirement and immunological consequences owing to its large size and outbred nature. In this study, we have cloned and constructed a canine minidystrophin gene vector. Owing to limited availability of the GRMD dogs, here we first examined the functions and therapeutic effects of the canine minidystrophin in the mdx mouse model. We observed efficient minigene expression without cellular immune responses in mdx mice after AAV1-cMinidys vector intramuscular injection. We also observed restoration of the missing dystrophin-associated protein complex (DPC) onto the sarcolemma, including sarcoglycans and dystrobrevin, and a partial restoration of a-syntrophin and neural nitric oxide synthase (nNOS). In addition, minidystrophin treatment ameliorated dystrophic pathology, such as fibrosis and myofiber central nucleation (CN). CN remained minimal (o2%) after AAV injection in the neonatal mdx mice and was reduced from more than 75% to about 25% after AAV injection in adult mdx mice. Finally, in vivo cell membrane leakage test with Evans blue dye showed that the canine minidystrophin could effectively protect the myofiber plasma membrane integrity. Our results, thus, demonstrated the functionality and therapeutic potential of the canine minidystrophin and paved its way for further testing in the GRMD dog model.

show abstract

Section: Introductionmentioning

confidence: 94%

A canine minidystrophin is functional and therapeutic in mdx mice

Wang

Qiao

et al. 2008

Gene Ther

View full text Add to dashboard Cite

show abstract

“…Skipping of exon 7 disrupts the mRNA reading frame and results in premature termination of translation. 47,48 Golden retriever crossbred dogs from a GRMD colony maintained in the Boisbonne Center for Gene Therapy of Oniris, NantesAtlantic College of Veterinary Medicine, Food Sciences and Engineering were studied. Affected dogs, which have progressive clinical dysfunction similar to that of DMD boys, as previously described, 45,49 were initially identified based on PCR-based genotyping, and the pathology confirmed by a dramatic elevation of serum creatine kinase.…”

Section: Animalsmentioning

confidence: 99%

Systemic Delivery of Allogenic Muscle Stem Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs

Rouger

Larcher

Dubreil

et al. 2011

The American Journal of Pathology

100

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is a genetic progressive muscle disease resulting from the lack of dystrophin and without effective treatment. Adult stem cell populations have given new impetus to cellbased therapy of neuromuscular diseases. One of them, muscle-derived stem cells, isolated based on delayed adhesion properties, contributes to injured muscle repair. However, these data were collected in dystrophic mice that exhibit a relatively mild tissue phenotype and clinical features of DMD patients. Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog's clinical status. These results demonstrate that MuStem cells could provide an attractive therapeutic avenue for DMD patients.

show abstract

“…102 However, the golden retriever muscular dystrophy has many advantages over the mdx mouse model, including severity of the disease resulting in early death, development of fibrosis and contractures, and homologous immune system. 103,104 The predictive value of outcome measures in these various animal models for human disease is unknown, and essentially unknowable, until there have been enough clinical successes of agents for muscle disease to take from the bedside back to the laboratory.…”

Section: Lack Of Validated Animal Modelsmentioning

confidence: 99%

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Wagner

2008

Neurotherapeutics

View full text Add to dashboard Cite

Summary:Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy. The cornerstones of current treatment include corticosteroids for skeletal muscle weakness, afterload reduction for cardiomyopathy, and noninvasive ventilation for respiratory failure. With these interventions, patients are walking and living longer. However, the current status is still far from adequate. Increased private and federal funding of studies in Duchenne muscular dystrophy has led to a large number of novel agents with propitious therapeutic potential. These include agents that modify dystrophin expression, increase muscle growth and regeneration, and modulate inflammatory responses. Many of these agents are already in clinical trials. Challenges to the development of additional novel therapeutics exist, including lack of validated animal models and lack of adequate biomarkers as surrogate endpoints. However, these challenges are not insurmountable and the next decade will likely see meaningful, new treatment options introduced into the clinical care of patients with Duchenne muscular dystrophy.

show abstract

The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs

Cited by 378 publications

References 17 publications

A canine minidystrophin is functional and therapeutic in mdx mice

A canine minidystrophin is functional and therapeutic in mdx mice

Systemic Delivery of Allogenic Muscle Stem Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Contact Info

Product

Resources

About