title: Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates.
abstract: Vectors based on adeno-associated viruses (AAVs) show promise for the treatment of genetic diseases. This study evaluates the biology of AAV-mediated gene transfer to liver in nonhuman primates (NHPs) using vectors based on AAV serotypes 2, 7, and 8. Transgenes encoding self-proteins were selected to minimize the confounding development of transgene-specific immune responses. These included the beta subunit of choriogonadotropic hormone (bCG) and erythropoietin (Epo), both derived from cDNAs from rhesus macaques. Experiments were performed with bCG in rhesus macaques and Epo in cynomolgus macaques. We demonstrated the previously untested hypothesis that preexisting immunity to a natural infection does substantially diminish the efficacy of gene transfer with a vector derived from an endogenous virus. Route of vector administration clearly has an impact on the development of immune responses to self-antigens. In general, efficiency of gene transfer to liver with AAV7 and 8 vectors was higher than what was achieved with AAV2, although a variety of host factors may influence this important parameter, such as preexisting immunity, gender, and transgene immunity.
authors.affiliation: Gene Therapy Program, Division of Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Grant
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Joanita
authors.initials: J
authors.lastname: Figueredo
authors.forename: Martin
authors.initials: M
authors.lastname: Lock
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D006063:Chorionic Gonadotropin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D007113:Immunity, Innate; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008253:Macaca mulatta
chemical_list: D001324:Autoantigens; D006063:Chorionic Gonadotropin; D004921:Erythropoietin