title: Systemic and Persistent Muscle Gene Expression in Rhesus Monkeys with a Liver De-Targeted Adeno-Associated Virus Vector.
abstract: The liver is a major off-target organ in gene therapy approaches for cardiac and musculoskeletal disorders. Intravenous administration of most of the naturally occurring adeno-associated virus (AAV) strains invariably results in vector genome sequestration within the liver. In the current study, we compared the muscle tropism and transduction efficiency of a liver de-targeted AAV variant to AAV9 following systemic administration in newborn rhesus monkeys. In vivo bioluminescence imaging was performed to monitor transgene expression (firefly luciferase) post administration. Results indicated comparable and sustained levels of systemic firefly luciferase gene expression in skeletal muscle over a period of two years. Quantitation of vector biodistribution in harvested tissues post-administration revealed widespread recovery of vector genomes delivered by AAV9 but markedly decreased levels in major systemic organs from the AAV variant. These studies validate the translational potential and safety of liver de-targeted AAV strains for gene therapy of muscle-related diseases.
authors.affiliation: 1 Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, California National Primate Research Center, University of California , Davis, California.|2 Departments of Pediatrics, University of California , Davis, California.|3 Cell Biology and Human Anatomy, University of California , Davis, California.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Tarantal
authors.affiliation: 1 Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, California National Primate Research Center, University of California , Davis, California.|2 Departments of Pediatrics, University of California , Davis, California.
authors.forename: C Chang I
authors.initials: CCI
authors.lastname: Lee
authors.affiliation: 1 Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, California National Primate Research Center, University of California , Davis, California.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Martinez
authors.affiliation: 4 Gene Therapy Center, University of North Carolina at Chapel Hill , North Carolina.
authors.forename: Aravind
authors.initials: A
authors.lastname: Asokan
authors.affiliation: 4 Gene Therapy Center, University of North Carolina at Chapel Hill , North Carolina.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006321:Heart / Q000503:physiopathology; D006331:Heart Diseases / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution; D014161:Transduction, Genetic
keywords: AAV9; Rhesus monkey; chimeric AAV; liver de-targeting