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

Guiner, Caroline Le; Servais, Laurent; Montus, M.; Larcher, Thibaut; Fraysse, Bodvaël; Moullec, Sophie; Allais, Marine; François, Virginie; Dutilleul, Maéva; Malerba, Alberto; Koo, Taeyoung; Thibaut, Jean-Laurent; Matot, Béatrice; Devaux, Marie Françoise; Duff, Johanne Le; Deschamps, Jack-Yves; Barthélémy, I.; Blot, Stéphane; Testault, Isabelle; Wahbi, Karim; Éderhy, Stéphane; Martin, Samia; Véron, Philippe; Georger, Christophe; Athanasopoulos, Takis; Masurier, Carole; Mingozzi, Federico; Carlier, Pierre; Gjata, Bernard; Hogrel, Jean‐Yves; Adjali, Oumeya; Mavilio, Fulvio; Voït, Thomas; Moullier, Philippe; Dickson, George

doi:10.1038/ncomms16105

Cited by 190 publications

(190 citation statements)

References 61 publications

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“…In the past years, treatment breakthroughs have been made in small and large animal models of NMDs (Bengtsson, Hall et al, 2017a, Bengtsson, Hall et al, 2017b, Childers, Joubert et al, 2014, Le Guiner, Servais et al, 2017, Malerba, Klein et al, 2017, Pozsgai, Griffin et al, 2017 and clinical benefits have been reported after a single injection of recombinant adeno-associated virus (rAAV) in patients with spinal muscular atrophy (Mendell, Al-Zaidy et al, 2017). In most of these studies, results consist of correlations between transgene expression levels and clinical outcome measures.…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Dupont

Guo

Lawlor

et al. 2018

Preprint

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Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Previous work from our laboratory on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrects structural abnormalities within the muscle and restores contractile function, with affected dogs surviving more than four years post injection. This exceptional therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology, and to what extent the whole muscle transcriptome is restored to normal after gene transfer.Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously-described canine cohort showing dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice, but also identified new transcripts linked to XLMTM pathology.We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created new metrics to pinpoint potential biomarkers of disease progression and correction.

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Section: Introductionmentioning

confidence: 99%

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Dupont

Guo

Lawlor

et al. 2018

Preprint

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“…However, a gradual loss of dystrophin-positive myofibers was seen during a 5-year follow up (220,222). Furthermore, the new study showed that limb perfusion of the U7snRNA AAV8 vectors did not induce the T cell response to newly synthesized dystrophin nor to AAV capsid (207). Cardiac rescue is attained with U7snRNA AAV6 vectors by percutaneous transendocardial delivery in the GRMD dog heart (219,221).…”

Section: Therapeutic Testing In the Canine Model And Impact On Patienmentioning

confidence: 89%

“…Micro-dystrophin also improved growth, increased limb muscle force, and enhanced activity and gait. Collectively, preclinical studies in the canine model have provided compelling supporting data for conducting systemic AAV micro-dystrophin therapy in human patients (204)(205)(206)(207)(208). Three independent clinical trials (conducted by Solid Bioscience, Pfizer, and Sarepta) are currently ongoing (209).…”

Section: Therapeutic Testing In the Canine Model And Impact On Patienmentioning

confidence: 99%

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

et al. 2020

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Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

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“…Pioneering translational research in the gene therapy and immunotherapy fields was conducted in dogs with hemophilia B , Duchenne muscular dystrophy and cancer , respectively. Such pioneering projects in dog models have accelerated the development of groundbreaking novel therapeutics for the parallel human disease .…”

Section: Current State Of Regenerative Medicine Research In Dogsmentioning

confidence: 99%

Concise Review: Canine Diabetes Mellitus as a Translational Model for Innovative Regenerative Medicine Approaches

Moshref

Tangey

Gilor

et al. 2019

Stem Cells Translational Medicine

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Diabetes mellitus (DM) is a common spontaneous endocrine disorder in dogs, which is defined by persistent hyperglycemia and insulin deficiency. Like type 1 diabetes (T1D) in people, canine DM is a complex and multifactorial disease in which genomic and epigenomic factors interact with environmental cues to induce pancreatic β‐cell loss and insulin deficiency, although the pathogenesis of canine DM is poorly defined and the role of autoimmunity is further controversial. Both diseases are incurable and require life‐long exogenous insulin therapy to maintain glucose homeostasis. Human pancreatic islet physiology, size, and cellular composition is further mirrored by canine islets. Although pancreatic or isolated islets transplantation are the only clinically validated methods to achieve long‐term normoglycemia and insulin independence, their availability does not meet the clinical need; they target a small portion of patients and have significant potential adverse effects. Therefore, providing a new source for β‐cell replacement is an unmet need. Naturally occurring DM in pet dogs, as a translational platform, is an untapped resource for various regenerative medicine applications that may offer some unique advantages given dogs' large size, longevity, heterogenic genetic background, similarity to human physiology and pathology, and long‐term clinical management. In this review, we outline different strategies for curative approaches, animal models used, and consider the value of canine DM as a translational animal/disease model for T1D in people. stem cells translational medicine 2019;8:450–455

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

Cited by 190 publications

References 61 publications

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

Concise Review: Canine Diabetes Mellitus as a Translational Model for Innovative Regenerative Medicine Approaches

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