Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs

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dc.contributor.authorMack, David L.en
dc.contributor.authorPoulard, Karineen
dc.contributor.authorGoddard, Melissa A.en
dc.contributor.authorLatoumerie, Virginieen
dc.contributor.authorSnyder, Jessica M.en
dc.contributor.authorGrange, Robert W.en
dc.contributor.authorElverman, Matthew R.en
dc.contributor.authorDenard, Jeromeen
dc.contributor.authorVeron, Philippeen
dc.contributor.authorBuscara, Laurineen
dc.contributor.authorLe Bec, Christineen
dc.contributor.authorHogrel, Jean-Yvesen
dc.contributor.authorBrezovec, Annie G.en
dc.contributor.authorMeng, Huien
dc.contributor.authorYang, Linen
dc.contributor.authorLiu, Fujunen
dc.contributor.authorO'Callaghan, Michaelen
dc.contributor.authorGopal, Nikhilen
dc.contributor.authorKelly, Valerie E.en
dc.contributor.authorSmith, Barbara K.en
dc.contributor.authorStrande, Jennifer L.en
dc.contributor.authorMavilio, Fulvioen
dc.contributor.authorBeggs, Alan H.en
dc.contributor.authorMingozzi, Federicoen
dc.contributor.authorLawlor, Michael W.en
dc.contributor.authorBuj-Bello, Anaen
dc.contributor.authorChilders, Martin K.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2019-10-07T13:35:53Zen
dc.date.available2019-10-07T13:35:53Zen
dc.date.issued2017-04-05en
dc.description.abstractX-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-speCific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.en
dc.description.notesWe thank Emily Troiano for assistance with genotyping the dogs. Some microscopic images were obtained using the Children's Hospital of Wisconsin Research Institute's Imaging Core Facility. EM was performed using the Medical College of Wisconsin's EM Core Facility. We thank Arthur Guilford for assistance with the manuscript; Kate Sweeney, at the University of Washington Visual Design and Production, who created the anatomical drawings found in several figures, but especially for her conceptual and artistic contributions on the VCN and transgene expression figures; Margaret Beatka in Pediatric Pathology at the Medical College of Wisconsin for graphic design; and Emma James of Audentes Therapeutics for editorial assistance. This work was supported in part by NIH grants R21 AR064503 and R01 HL115001 to M.K.C., grant K08 AR059750 to M.W.L., grant K08 HL111148 to J.L.S., grants R01AR044345 and HD075802 and MDA383249 (Muscular Dystrophy Association) to A.H.B.; the Senator Paul D Wellstone Muscular Dystrophy Cooperative Research Center, Seattle (NIH grant U54AR065139); the Muscular Dystrophy Association (M.K.C.); the Association Francaise contre les Myopathies (AFM-Telethon) (A.B.-B. and M.K.C.); the Myotubular Trust, UK (A.B.-B.); Where There's a Will There's a Cure (A.H.B. and M.K.C.); the Joshua Frase Foundation (A.H.B. and M.K.C.), the Peter Khuri Myopathy Research Foundation (M.K.C.); and Audentes Therapeutics (M.K.C., M.W.L., A.H.B., and A.B.-B.).en
dc.description.sponsorshipNIH [R21 AR064503, R01 HL115001, K08 AR059750, K08 HL111148, R01AR044345, HD075802, MDA383249]; Senator Paul D Wellstone Muscular Dystrophy Cooperative Research Center, Seattle (NIH) [U54AR065139]; Muscular Dystrophy Association; Association Francaise contre les Myopathies (AFM-Telethon); Myotubular Trust, UK; Where There's a Will There's a Cure; Joshua Frase Foundation; Peter Khuri Myopathy Research Foundation; Audentes Therapeuticsen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.ymthe.2017.02.004en
dc.identifier.eissn1525-0024en
dc.identifier.issn1525-0016en
dc.identifier.issue4en
dc.identifier.pmid28237839en
dc.identifier.urihttp://hdl.handle.net/10919/94380en
dc.identifier.volume25en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.titleSystemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogsen
dc.title.serialMolecular Therapyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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