Dataset Information

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

ABSTRACT: Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.

SUBMITTER: Le Guiner C

PROVIDER: S-EPMC5537486 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Le Guiner Caroline C Servais Laurent L Montus Marie M Larcher Thibaut T Fraysse Bodvaël B Moullec Sophie S Allais Marine M François Virginie V Dutilleul Maeva M Malerba Alberto A Koo Taeyoung T Thibaut Jean-Laurent JL Matot Béatrice B Devaux Marie M Le Duff Johanne J Deschamps Jack-Yves JY Barthelemy Inès I Blot Stéphane S Testault Isabelle I Wahbi Karim K Ederhy Stéphane S Martin Samia S Veron Philippe P Georger Christophe C Athanasopoulos Takis T Masurier Carole C Mingozzi Federico F Carlier Pierre P Gjata Bernard B Hogrel Jean-Yves JY Adjali Oumeya O Mavilio Fulvio F Voit Thomas T Moullier Philippe P Dickson George G

Nature communications 20170725

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on ...[more]

PMID: 28742067

Similar Datasets

Project description:Duchenne muscular dystrophy (DMD) causes progressive disability in 1 of every 5,000 boys due to the lack of functional dystrophin protein. Despite much advancement in knowledge about DMD disease presentation and progression-attributable in part to studies using mouse and canine models of the disease-current DMD treatments are not equally effective in all patients. There remains, therefore, a need for translational animal models in which novel treatment targets can be identified and evaluated. Golden Retriever muscular dystrophy (GRMD) is a phenotypically and genetically homologous animal model of DMD. As with DMD, speed of disease progression in GRMD varies substantially. However, unlike DMD, all GRMD dogs possess the same causal mutation; therefore genetic modifiers of phenotypic variation are relatively easier to identify. Furthermore, the GRMD dogs used in this study reside within the same colony, reducing the confounding effects of environment on phenotypic variation. To detect modifiers of disease progression, we developed gene expression profiles using RNA sequencing for 9 dogs: 6 GRMD dogs (3 with faster-progressing and 3 with slower-progressing disease, based on quantitative, objective biomarkers) and 3 control dogs from the same colony. All dogs were evaluated at 2 time points: early disease onset (3 months of age) and the point at which GRMD stabilizes (6 months of age) using quantitative, objective biomarkers identified as robust against the effects of relatedness/inbreeding. Across all comparisons, the most differentially expressed genes fell into 3 categories: myogenesis/muscle regeneration, metabolism, and inflammation. Our findings are largely in concordance with DMD and mouse model studies, reinforcing the utility of GRMD as a translational model. Novel findings include the strong up-regulation of chitinase 3-like 1 (CHI3L1) in faster-progressing GRMD dogs, suggesting previously unexplored mechanisms underlie progression speed in GRMD and DMD. In summary, our findings support the utility of RNA sequencing for evaluating potential biomarkers of GRMD progression speed, and are valuable for identifying new avenues of exploration in DMD research.

Project description:Duchenne muscular dystrophy (DMD) is a lethal disease caused by X-linked mutations in the dystrophin gene. Dystrophin deficiency results in progressive degeneration of cardiac, respiratory and skeletal muscles leading to premature death due to cardiopulmonary complications. Currently, no cure exists for DMD. Based on our previous reports confirming a protective effect of human dystrophin expressing chimeric (DEC) cell therapy on cardiac, respiratory, and skeletal muscle function after intraosseous administration, now we assessed long-term safety and biodistribution of human DEC therapy for potential clinical applications in DMD patients. Safety of different DEC doses (1 × 106 and 5 × 106) was assessed at 180 days after systemic-intraosseous administration to mdx/scid mice, a model of DMD. Assessments included: single cell gel electrophoresis assay (COMET assay) to confirm lack of genetic toxicology, magnetic resonance imaging (MRI) for tumorigenicity, and body, muscle and organ weights. Human DEC biodistribution to the target (heart, diaphragm, gastrocnemius muscle) and non-target (blood, bone marrow, lung, liver, spleen) organs was detected by flow cytometry assessment of HLA-ABC markers. Human origin of dystrophin was verified by co-localization of dystrophin and human spectrin by immunofluorescence. No complications were observed after intraosseous transplant of human DEC. COMET assay of donors and fused DEC cells confirmed lack of DNA damage. Biodistribution analysis of HLA-ABC expression revealed dose-dependent presence of human DEC cells in target organs, whereas negligible presence was detected in non-target organs. Human origin of dystrophin in the heart, diaphragm and gastrocnemius muscle was confirmed by co-localization of dystrophin expression with human spectrin. MRI revealed no evidence of tumor formation. Body mass and muscle and organ weights were stable and comparable to vehicle controls, further confirming DEC safety at 180 days post- transplant. This preclinical study confirmed long-term local and systemic safety of human DEC therapy at 180 days after intraosseous administration. Thus, DEC can be considered as a novel myoblast based advanced therapy medicinal product for DMD patients.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets