Efficient and Targeted Transduction of Nonhuman Primate Liver With Systemically Delivered Optimized AAV3B Vectors
Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Viral Vector Core; Department of Pediatrics, Division of Pulmonary and Allergy; Program in Molecular Medicine
Genetics and Genomics | Molecular Biology | Therapeutics
Recombinant adeno-associated virus serotype 3B (rAAV3B) can transduce cultured human liver cancer cells and primary human hepatocytes efficiently. Serine (S)- and threonine (T)-directed capsid modifications further augment its transduction efficiency. Systemically delivered capsid-optimized rAAV3B vectors can specifically target cancer cells in a human liver cancer xenograft model, suggesting their potential use for human liver-directed gene therapy. Here, we compared transduction efficiencies of AAV3B and AAV8 vectors in cultured primary human hepatocytes and cancer cells as well as in human and mouse hepatocytes in a human liver xenograft NSG-PiZ mouse model. We also examined the safety and transduction efficacy of wild-type (WT) and capsid-optimized rAAV3B in the livers of nonhuman primates (NHPs). Intravenously delivered S663V+T492V (ST)-modified self-complementary (sc) AAV3B-EGFP vectors led to liver-targeted robust enhanced green fluorescence protein (EGFP) expression in NHPs without apparent hepatotoxicity. Intravenous injections of both WT 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 toxicity. Our studies should be important and informative for clinical development of optimized AAV3B vectors for human liver-directed gene therapy.
DOI of Published Version
Mol Ther. 2015 Dec;23(12):1867-76. doi: doi:10.1038/mt.2015.174. Epub 2015 Sep 25. Link to article on publisher's site
Molecular therapy : the journal of the American Society of Gene Therapy
Li S, Zhong L, Li M, Su Q, He R, Tang Q, Greiner DL, Brehm MA, Flotte TR, Mueller C, Gao G. (2015). Efficient and Targeted Transduction of Nonhuman Primate Liver With Systemically Delivered Optimized AAV3B Vectors. Pediatric Publications. https://doi.org/10.1038/mt.2015.174. Retrieved from https://escholarship.umassmed.edu/peds_pp/64