Matthew Elverman1, Melissa A Goddard2, David Mack1,3, Jessica M Snyder4, Michael W Lawlor5, Hui Meng5, Alan H Beggs6, Ana Buj-Bello7, Karine Poulard7, Anthony P Marsh8, Robert W Grange9, Valerie E Kelly1, Martin K Childers1,3. 1. Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA. 2. Department of Physiology and Pharmacology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA. 3. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. 4. Department of Comparative Medicine, University of Washington, Campus Box 357340, Seattle, Washington, USA. 5. Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 6. Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7. Généthon, INSERM UMR S951, Evry, France. 8. Department of Health and Exercise Science, Wake Forest University, Winston-Salem, North Carolina, USA. 9. Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
Abstract
INTRODUCTION: X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. METHODS: We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression. RESULTS: Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength. CONCLUSIONS: AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017.
INTRODUCTION:X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. METHODS: We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression. RESULTS: Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTMdogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength. CONCLUSIONS:AAV-mediated gene transfer of MTM1 in young XLMTMdogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017.
Authors: Kimberly Amburgey; Nancy McNamara; Lindsey R Bennett; M Eileen McCormick; Gyula Acsadi; James J Dowling Journal: Ann Neurol Date: 2011-10 Impact factor: 10.422
Authors: Jahannaz Dastgir; Anne Rutkowski; Rachel Alvarez; Stacy A Cossette; Ke Yan; Raymond G Hoffmann; Caroline Sewry; Yukiko K Hayashi; Hans-Hilmar Goebel; Carsten Bonnemann; Michael W Lawlor Journal: Arch Pathol Lab Med Date: 2015-07-01 Impact factor: 5.534
Authors: M Kristiansen; G P Knudsen; S M Tanner; M McEntagart; H Jungbluth; F Muntoni; C Sewry; S Gallati; K H Ørstavik; C Wallgren-Pettersson Journal: Neuromuscul Disord Date: 2003-08 Impact factor: 4.296
Authors: Hui Meng; Paul M L Janssen; Robert W Grange; Lin Yang; Alan H Beggs; Lindsay C Swanson; Stacy A Cossette; Alison Frase; Martin K Childers; Henk Granzier; Emanuela Gussoni; Michael W Lawlor Journal: J Vis Exp Date: 2014-07-15 Impact factor: 1.355
Authors: G Diane Shelton; Katie M Minor; Ling T Guo; Steven G Friedenberg; Jonah N Cullen; Jeffrey M Hord; David Venzke; Mary E Anderson; Megan Devereaux; Sally J Prouty; Caryl Handelman; Kevin P Campbell; James R Mickelson Journal: Neuromuscul Disord Date: 2021-07-28 Impact factor: 4.296
Authors: Michael D Fox; Vincent J Carson; Han-Zhong Feng; Michael W Lawlor; John T Gray; Karlla W Brigatti; J-P Jin; Kevin A Strauss Journal: Hum Mol Genet Date: 2018-09-15 Impact factor: 6.150
Authors: Mohammadsharif Tabebordbar; Kim A Lagerborg; Alexandra Stanton; Emily M King; Simon Ye; Liana Tellez; Allison Krunnfusz; Sahar Tavakoli; Jeffrey J Widrick; Kathleen A Messemer; Emily C Troiano; Behzad Moghadaszadeh; Bryan L Peacker; Krystynne A Leacock; Naftali Horwitz; Alan H Beggs; Amy J Wagers; Pardis C Sabeti Journal: Cell Date: 2021-09-09 Impact factor: 66.850
Authors: Jean-Baptiste Dupont; Jianjun Guo; Edith Renaud-Gabardos; Karine Poulard; Virginie Latournerie; Michael W Lawlor; Robert W Grange; John T Gray; Ana Buj-Bello; Martin K Childers; David L Mack Journal: Mol Ther Date: 2019-11-11 Impact factor: 11.454