Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy.
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.
Jiang
Haiyan
H
Bayer HealthCare Pharmaceuticals, 800 Dwight Way, Berkeley, CA 94710, USA. haiyan.jiang.b@bayer.com
Couto
Linda B
LB
Patarroyo-White
Susannah
S
Liu
Tongyao
T
Nagy
Dea
D
Vargas
Joseph A
JA
Zhou
Shangzhen
S
Scallan
Ciaran D
CD
Sommer
Jurg
J
Vijay
Sharmila
S
Mingozzi
Federico
F
High
Katherine A
KA
Pierce
Glenn F
GF
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
D000906:Antibodies; D005164:Factor IX; D009173:Mycophenolic Acid; D016559:Tacrolimus