title: Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy.
abstract: In a clinical study of recombinant adeno-associated virus-2 expressing human factor IX (AAV2-FIX), we detected 2 impediments to long-term gene transfer. First, preexisting anti-AAV neutralizing antibodies (NABs) prevent vector from reaching the target tissue, and second, CD8(+) T-cell responses to hepatocyte-cell surface displayed AAV-capsid-terminated FIX expression after several weeks. Because the vector is incapable of synthesizing viral proteins, a short course of immunosuppression, until AAV capsid is cleared from the transduced cells, may mitigate the host T-cell response, allowing long-term expression of FIX. To evaluate coad-ministration of immunosuppression, we studied AAV8 vector infusion in rhesus macaques, natural hosts for AAV8. We administered AAV8-FIX in 16 macaques via the hepatic artery and assessed the effects of (1) preexisting anti-AAV8 NABs, (2) a standard T-cell immunosuppressive regimen, and (3) efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NABs abrogate transduction, whereas animals with undetectable NABs are safely and effectively transduced by AAV8-FIX. Coadministration of mycophenolate mofetil and tacrolimus with vector does not induce toxicity and does not impair AAV transduction or FIX synthesis. These findings enable a clinical study to assess the effects of immunomodulation on long-term FIX expression in patients with hemophilia B.
authors.affiliation: Bayer HealthCare Pharmaceuticals, 800 Dwight Way, Berkeley, CA 94710, USA. haiyan.jiang.b@bayer.com
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Linda B
authors.initials: LB
authors.lastname: Couto
authors.forename: Susannah
authors.initials: S
authors.lastname: Patarroyo-White
authors.forename: Tongyao
authors.initials: T
authors.lastname: Liu
authors.forename: Dea
authors.initials: D
authors.lastname: Nagy
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vargas
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Ciaran D
authors.initials: CD
authors.lastname: Scallan
authors.forename: Jurg
authors.initials: J
authors.lastname: Sommer
authors.forename: Sharmila
authors.initials: S
authors.lastname: Vijay
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004359:Drug Therapy, Combination; D005164:Factor IX / Q000008:administration & dosage / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology / Q000493:pharmacokinetics; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods* / Q000592:standards; D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D009928:Organ Specificity; D016559:Tacrolimus / Q000008:administration & dosage
chemical_list: D000906:Antibodies; D005164:Factor IX; D009173:Mycophenolic Acid; D016559:Tacrolimus