Song Y, Morales L, Malik AS, et al. Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models. Nature medicine 2019
The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin(1), a rod-like protein(2) that protects striated myocytes from contraction-induced injury(3,4). Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin(5). Importantly, normal thymic expression in DMD patients(6) should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (microUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that microUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-microUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, microUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of microUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed microDystrophin (microDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.