A paper published earlier this year in Molecular Therapy detailed a successful dose dependent response of a usually fatal monogenic disorder of skeletal muscle in dogs to gene therapy. The disorder treated was X-Linked Myotubular Myopathy (XLMTM) which results from MTM1 gene mutations and deficiency in the protein that this gene encodes (myotubularin). Dogs affected by this inherited neuromuscular disease had an intravenous infusion of a viral vector (a recombinant adeno-associated virus) carrying the correct gene.
XLMTM induces a rapidly progressing diffuse muscular weakness with respiratory and gastric compromise which is generally fatal. In human medicine intensive intervention is required to improve longevity.
Neurological assessment, movement, reflex scores and respiratory function were all utilised to quantify the dose dependent response to treatment in the study participants. The analysis included in this paper show a clear improvement in parameters with each subsequent increase in dose. With intravenous administration a diffuse whole body biodistribution was attained and documented at postmortem.
In both mice and dog models gene replacement therapy has been shown to be effective. The next step is translational to clinical trials for human application.
In conclusion, our results demonstrate that systemic administration of rAAV8-cMTM1 can correct the severe generalized muscle disease in myotubularin-deficient dogs, defining a threshold dose in this an- imal model, and support clinical trials of gene therapy in patients with XLMTM by simple vector injection into a peripheral vein.
The UWMedicineHealth YouTube channel has a video with the lead author on this study here.
Mack, David L. et al. (2017) Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs. Molecular Therapy , Volume 25 , Issue 4 , 839 - 854. doi:10.1016/j.ymthe.2017.02.004
Beggs, Alan H. et al. (2010) MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. PNAS August 17, 2010 vol. 107 no. 33 doi:10.1073/pnas.1003677107.