Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.
- Additional Document Info
- View All
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 (Utro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that Utro 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-Utro 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, Utro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of Utro 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 Dystrophin (Dystro). 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.
author list (cited authors)
Song, Y., Morales, L., Malik, A. S., Mead, A. F., Greer, C. D., Mitchell, M. A., ... Stedman, H. H.
complete list of authors
Song, Yafeng||Morales, Leon||Malik, Alock S||Mead, Andrew F||Greer, Christopher D||Mitchell, Marilyn A||Petrov, Mihail T||Su, Leonard T||Choi, Margaret E||Rosenblum, Shira T||Lu, Xiangping||VanBelzen, Daniel J||Krishnankutty, Ranjith K||Balzer, Frederick J||Loro, Emanuele||French, Robert||Propert, Kathleen J||Zhou, Shangzhen||Kozyak, Benjamin W||Nghiem, Peter P||Khurana, Tejvir S||Kornegay, Joe N||Stedman, Hansell H