%0 Journal Article
%T Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates
%A Carmen Unzu
%A Sandra Herv¨¢s-Stubbs
%A Ana Sampedro
%A Itsaso Mauleon
%A Uxua Manche£¿o
%A Carlos Alfaro
%A Rafael Enr¨ªquez de Salamanca
%A Alberto Benito
%A Stuart G Beatties
%A Harald Pety
%A Jes¨²s Prieto
%A Ignacio Melero
%A Antonio Fontanellas
%J Journal of Translational Medicine
%D 2012
%I BioMed Central
%R 10.1186/1479-5876-10-122
%X Three female Macaca fascicularis were intravenously injected with 1x1013 genome copies/kg of rAAV5 encoding the human PBGD. Mycophenolate mofetil (MMF), anti-thymocyte immunoglobulin, methylprednisolone, tacrolimus and rituximab were given in combination during 12£¿weeks to block T- and B-cell mediated adaptive immune responses in two macaques. Immunodeficient and immunocompetent mice were intravenously injected with 5x1012 genome copies/kg of rAAV5-encoding luciferase protein. Forty days later MMF, tacrolimus and rituximab were daily administrated to ascertain whether the immunosuppressants or their metabolites could interfere with transgene expression.Macaques given a rAAV5 vector encoding human PBGD developed cellular and humoral immunity against viral capsids but not towards the transgene. Anti-AAV humoral responses were attenuated during 12£¿weeks but intensely rebounded following cessation of the immunosuppressants. Accordingly, subsequent gene transfer with a rAAV5 vector encoding green fluorescent protein was impossible. One macaque showed enhanced PBGD expression 25£¿weeks after rAAV5-pbgd administration but overexpression had not been detected while the animal was under immunosuppression. As a potential explanation, MMF decreases transgene expression in mouse livers that had been successfully transduced by a rAAV5 several weeks before MMF onset. Such a silencing effect was independent of AAV complementary strand synthesis and requires an adaptive immune system.These results indicate that our transient and intensive pharmacological immunosuppression fails to improve AAV5-based liver gene transfer in non-human primates. The reasons include an incomplete restraint of humoral immune responses to viral capsids that interfere with repeated gene transfer in addition to an intriguing MMF-dependent drug-mediated interference with liver transgene expression.
%K Adeno-associated virus serotype 5
%K Neutralizing antibodies
%K Re-administration
%K Vector Immunology/Host Responses
%K Immunomodulation
%U http://www.translational-medicine.com/content/10/1/122/abstract