Efficient and Targeted Transduction of Nonhuman Primate Liver With Systemically Delivered Optimized XXXX B Vectors.

@entity1 @entity137 @entity96 @entity5 @entity19 @entity73275 @entity73274 @entity164 @entity563 @entity1889 @entity21481
UNASSIGNED: Recombinant adeno-associated virus serotype 3B (rAAV3B) can transduce cultured @entity1 @entity96 cells and primary @entity1 hepatocytes efficiently. @entity563 (S)- and @entity1889 (T)-directed capsid modifications further augment its transduction efficiency. Systemically delivered capsid-optimized rAAV3B vectors can specifically target @entity5 cells in a @entity1 @entity96 xenograft model, suggesting their potential use for @entity1 liver-directed gene therapy. Here, we compared transduction efficiencies of @entity21481 B and AAV8 vectors in cultured primary @entity1 hepatocytes and @entity5 cells as well as in @entity1 and @entity19 hepatocytes in a @entity1 liver xenograft NSG-PiZ @entity19 model. We also examined the safety and transduction efficacy of @entity164 ( @entity164 ) and capsid-optimized rAAV3B in the livers of nonhuman primates (NHPs). Intravenously delivered @entity73274 + @entity73275 (ST)-modified self-complementary (sc) @entity21481 B-EGFP vectors led to liver-targeted robust enhanced green fluorescence protein (EGFP) expression in NHPs without apparent hepatotoxicity. Intravenous injections of both @entity164 and ST-modified rAAV3B.ST-rhCG vectors also generated stable super-physiological levels of rhesus chorionic gonadotropin (rhCG) in NHPs. The vector genome predominantly targeted the liver. Clinical chemistry and histopathology examinations showed no apparent vector-related @entity137 . Our studies should be important and informative for clinical development of optimized @entity21481 B vectors for @entity1 liver-directed gene therapy.Molecular Therapy (2015); doi:10.1038/mt.2015.174.
