X-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.

Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs / Mack, D. L.; Poulard, K.; Goddard, M. A.; Latournerie, V.; Snyder, J. M.; Grange, R. W.; Elverman, M. R.; Denard, J.; Veron, P.; Buscara, L.; Le Bec, C.; Hogrel, J. -Y.; Brezovec, A. G.; Meng, H.; Yang, L.; Liu, F.; O'Callaghan, M.; Gopal, N.; Kelly, V. E.; Smith, B. K.; Strande, J. L.; Mavilio, F.; Beggs, A. H.; Mingozzi, F.; Lawlor, M. W.; Buj-Bello, A.; Childers, M. K.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 25:4(2017), pp. 839-854. [10.1016/j.ymthe.2017.02.004]

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

Mavilio F.;
2017

Abstract

X-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.
2017
22-feb-2017
25
4
839
854
Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs / Mack, D. L.; Poulard, K.; Goddard, M. A.; Latournerie, V.; Snyder, J. M.; Grange, R. W.; Elverman, M. R.; Denard, J.; Veron, P.; Buscara, L.; Le Bec, C.; Hogrel, J. -Y.; Brezovec, A. G.; Meng, H.; Yang, L.; Liu, F.; O'Callaghan, M.; Gopal, N.; Kelly, V. E.; Smith, B. K.; Strande, J. L.; Mavilio, F.; Beggs, A. H.; Mingozzi, F.; Lawlor, M. W.; Buj-Bello, A.; Childers, M. K.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 25:4(2017), pp. 839-854. [10.1016/j.ymthe.2017.02.004]
Mack, D. L.; Poulard, K.; Goddard, M. A.; Latournerie, V.; Snyder, J. M.; Grange, R. W.; Elverman, M. R.; Denard, J.; Veron, P.; Buscara, L.; Le Bec, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1199451
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