Audentes is developing AT132 for the treatment of X-Linked Myotubular Myopathy.
X-Linked Myotubular Myopathy is an ultra-rare, severe, debilitating condition that affects skeletal muscles, leading to severe muscle weakness (hypotonia) and profound respiratory distress, often requiring invasive ventilatory support. It affects an estimated one in 50,000 newborn males worldwide, and is caused by mutations in the MTM1 gene. These mutations lead to lack or dysfunction of the myotubularin protein, which, when functioning normally, is required for normal development, maturation and maintenance of muscle cells. For more information about X-Linked Myotubular Myopathy disease, please visit here.
The goal of gene therapy for X-Linked Myotubular Myopathy is long-term expression of myotubularin after administration of a vector carrying the MTM1 gene. Increased levels of myotubularin are expected to produce improvement in symptoms related to the disease. Early studies by Buj-Bello et al. demonstrated promising results in myotubularin-deficient mice after delivery of the MTM1 gene using an adeno-associated virus vector system. Treatment resulted in increased expression of the protein, improvement in muscle architecture, reversal of muscle hypotrophy, improvement in muscle strength, and an improvement in overall survival (Buj-Bello et al, Human Molecular Genetics, 2008, Vol. 17: 2132-2143; Buj-Bello et al., Molecular Therapy, 2013, 21:sup 1, S14).
There is also a spontaneously occurring MTM1 mutation in dogs (Beggs et al., PNAS, August 17, 2010, vol. 107: 14697-14702). Encouraging results from studies in this dog model were published in Science Translational Medicine (Childers et al., Sci Transl Med 22 January 2014 6:220ra10; http://stm.sciencemag.org/content/6/220/220ra10). Research teams from Genethon, the University of Washington, and Harvard University demonstrated that treatment with a single dose of adeno-associated virus carrying the gene deficient in X-Linked Myotubular Myopathy resulted in an increase in muscle strength, improved respiratory function, and prolonged survival. These data are the first demonstration of persistent disease correction in a large animal model of a neuromuscular disease through the delivery of a single, intravenous administration of adeno-associated virus.