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Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.
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.
Afiliación
  • Song Y; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Morales L; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Malik AS; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Mead AF; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Greer CD; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Mitchell MA; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Petrov MT; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Su LT; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Choi ME; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Rosenblum ST; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Lu X; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • VanBelzen DJ; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Krishnankutty RK; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Balzer FJ; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Loro E; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • French R; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Propert KJ; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zhou S; Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Kozyak BW; Department of Surgery, Pennsylvania Muscle Institute, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Nghiem PP; Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Khurana TS; Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA.
  • Kornegay JN; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Stedman HH; Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA.
Nat Med ; 25(10): 1505-1511, 2019 10.
Article en En | MEDLINE | ID: mdl-31591596
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Distrofia Muscular de Duchenne / Utrofina / Distrofias Musculares / Distrofia Muscular Animal Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Distrofia Muscular de Duchenne / Utrofina / Distrofias Musculares / Distrofia Muscular Animal Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos