Use of the dog model for Duchenne muscular dystrophy in gene therapy trials

Howell, John C.; Fletcher, Sue; Kakulas, Byron; O'Hara, M.; Lochmüller, Hanns; Karpati, George

doi:10.1016/s0960-8966(97)00057-6

Cited by 64 publications

(64 citation statements)

References 12 publications

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“…Conclusions and future perspectives Gene or cell therapy approaches for GRMD have until now produced negative 20 or modestly positive results [21][22][23] . We show here that it is possible to transplant mesoangioblasts into dystrophic dogs and obtain an extensive reconstitution of fibres expressing dystrophin, an improvement in the contraction force and, in many cases, a preservation of walking ability.…”

Section: Immune Reaction Against Dystrophin and Donor Cellsmentioning

confidence: 99%

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Sampaolesi

Blot

D’Antona

et al. 2006

Nature

677

569

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Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.

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Section: Immune Reaction Against Dystrophin and Donor Cellsmentioning

confidence: 99%

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Sampaolesi

Blot

D’Antona

et al. 2006

Nature

677

569

View full text Add to dashboard Cite

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“…26 All animals were cared and treated in accordance with the guidelines approved by Ethics Committee for Treatment of Laboratory Animals at NCNP or Animal Ethics Committee at Murdoch University, where three fundamental principles (replacement, reduction and refinement) were also considered. When a rAAV was injected into dogs, the animals were not vaccinated to relive influences of immune response by vaccination.…”

Section: Construction and Production Of Raavsmentioning

confidence: 99%

Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products

et al. 2007

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Using murine models, we have previously demonstrated that recombinant adeno-associated virus (rAAV)-mediated microdystrophin gene transfer is a promising approach to treatment of Duchenne muscular dystrophy (DMD). To examine further therapeutic effects and the safety issue of rAAV-mediated microdystrophin gene transfer using larger animal models, such as dystrophic dog models, we first investigated transduction efficiency of rAAV in wild-type canine muscle cells, and found that rAAV2 encoding b-galactosidase effectively transduces canine primary myotubes in vitro. Subsequent rAAV2 transfer into skeletal muscles of normal dogs, however, resulted in low and transient expression of b-galactosidase together with intense cellular infiltrations in vivo, where cellular and humoral immune responses were remarkably activated.In contrast, rAAV2 expressing no transgene elicited no cellular infiltrations. Co-administration of immunosuppressants, cyclosporine and mycophenolate mofetil could partially improve rAAV2 transduction. Collectively, these results suggest that immune responses against the transgene product caused cellular infiltration and eliminated transduced myofibers in dogs. Furthermore, in vitro interferon-g release assay showed that canine splenocytes respond to immunogens or mitogens more susceptibly than murine ones. Our results emphasize the importance to scrutinize the immune responses to AAV vectors in larger animal models before applying rAAV-mediated gene therapy to DMD patients.

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“…É caracterizada por contínua necrose muscular e degeneração, com eventual fibrose e infiltração por tecido adiposo (Howell et al 1997). Sua fisiopatologia é determinada pela ausência ou disfunção da distrofina, proteí-na encontrada numa variedade de tecidos, principalmente nas musculaturas esquelética e cardíaca, nervos e regiões específicas do sistema nervoso central.…”

Section: Introductionunclassified

Influência do bloqueador de receptor de angiotensina (Losartana potássica) na função renal e pressão arterial em cães GRMD

et al. 2009

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A distrofia muscular de Duchenne (DMD) é uma alteração neuromuscular caracterizada por contínua necrose muscular e degeneração, com eventual fibrose e infiltração por tecido adiposo. O aumento progressivo da fibrose intersticial no músculo impede a migração das células miogênicas, necessárias para a formação muscular. O modelo canino constitui-se nas melhores fenocópias da doença em humanos, quando comparados com outros modelos animais com distrofia. O tratamento antifibrose de pacientes DMD, tendo como alvo os mediadores da citocina, TGF-beta, e o tratamento com antiinflamatórios, podem limitar a degeneração muscular e contribuir para a melhora do curso da doença. O presente estudo teve como objetivo observar os possíveis efeitos adversos na fisiologia renal, por meio de avaliação bioquímica sanguínea e da pressão arterial, verificando a viabilidade do uso do Losartan (um inibidor de TGF-beta) nos cães afetados pela distrofia muscular. Foram utilizados quatro cães adultos, sendo dois machos e duas fêmeas. Utilizou-se a dose de 50mg de Losartan, administrada via oral, uma vez ao dia. Os exames clínicos, bem como alterações na função renal, o nível do potássio sérico e a pressão arterial não evidenciaram reação adversa durante todo o período do experimento. O uso de Losartan, por um período de 9 semanas, mostrou-se como uma terapia segura para o tratamento antifibrótico em cães adultos, não afetando a função renal ou pressão arterial dos animais.

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Use of the dog model for Duchenne muscular dystrophy in gene therapy trials

Cited by 64 publications

References 12 publications

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products

Influência do bloqueador de receptor de angiotensina (Losartana potássica) na função renal e pressão arterial em cães GRMD

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