1. Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models
- Author
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Kathleen J. Propert, Xiangping Lu, Margaret E Choi, Frederick J. Balzer, Shira T. Rosenblum, Daniel J VanBelzen, Leonard T. Su, Peter P. Nghiem, Joe N. Kornegay, Marilyn A. Mitchell, Mihail Petrov, Shangzhen Zhou, Benjamin W. Kozyak, Christopher D. Greer, Alock Malik, Yafeng Song, Andrew F. Mead, Ranjith K Krishnankutty, Robert A. French, Hansell H. Stedman, Emanuele Loro, Leon Morales, and Tejvir S. Khurana
- Subjects
musculoskeletal diseases ,0301 basic medicine ,biology ,business.industry ,Genetic enhancement ,Transgene ,Duchenne muscular dystrophy ,Regeneration (biology) ,General Medicine ,musculoskeletal system ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Utrophin ,biology.protein ,Cancer research ,Medicine ,Muscular dystrophy ,business ,Dystrophin ,Immunologic Tolerance - Abstract
The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro 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-µUtro 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, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro 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 µDystrophin (µDystro). 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.
- Published
- 2019
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