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• W2561620555 abstract "Gene transfer approaches based on the adeno-associated virus (AAV) vector platform have shown great therapeutic potential in both preclinical studies and clinical trials. Neutralizing immune responses to AAV, however, are an important limitation to the use of AAV vectors as therapeutic tools, as even low-titer anti-capsid neutralizing antibodies (NAb) can lead to vector clearance and lack of efficacy. In particular, anti-AAV NAbs develop at high titers following vector administration and persist for several years after AAV vector administration, making vector re-administration hard if not impossible. Here we tested a novel strategy to modulate immune responses directed against AAV vectors based on the co-administration of biodegradable tolerogenic poly(lactic acid co-glycolytic acid) (PLGA) nanoparticles (tNP) containing rapamycin at the time of vector administration. C57BL/6 mice (n=5/group) received an AAV8 vector encoding for luciferase (AAV8-Luc) at a dose of 4×1012 vg/kg injected intravenously alone, or formulated with empty PLGA nanoparticles (NP), or formulated with tNP containing 100 µg of rapamycin. Three weeks after treatment, anti-AAV8 antibodies were measured and animals received a second intravenous infusion with an AAV8 vector encoding for human coagulation factor IX (AAV8-hFIX) at a dose of 4×1012 vg/kg formulated with NP or tNP. An anti-AAV8 antibody ELISA and an in vitro neutralization assay was used to follow humoral immune responses to the vector. While no development of anti-AAV8 antibodies was observed in the tNP-treated animals after the first and second vector administration, control groups developed robust humoral immune responses to the AAV8 capsid, which prevented vector readministration. Consequently, efficient hFIX transgene expression deriving from the second AAV8 vector administration was observed only when tNP were used, at levels identical to animals that received only a single administration of AAV8-hFIX. Lack of antibody formation against the AAV8 capsid in animals treated with tNP was also accompanied by a downregulation of both CD4+ and CD8+ T cell responses in the liver. A mild decrease in the frequency of CD4+ T cells in spleen, with no change in frequency of regulatory T cells, were also noted. In a separate set of experiments, we tested the antigen-specificity of the treatment of tNP with AAV8 administration. Mice (n=5/group) received 4×1012 vg/kg of an AAV8-luc vector with tNP followed by either challenge with hFIX protein in complete Freund's adjuvant, AAV5-hFIX vector intravenous injection, or AAV8-hFIX vector intravenous injection. All animals pretreated with AAV8-luc and tNP developed antibodies against the hFIX and the AAV5 antigens, while they anti-AAV8 antibody titers were significantly decreased. In conclusion, tNP administration together withAAV vector prevents anti-capsid immune responses in an antigen-specific manner and allows for AAV vector readministration, addressing one of the most important challenges of the in vivo gene transfer field." @default.
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• W2561620555 date "2016-05-01" @default.
• W2561620555 modified "2023-10-18" @default.
• W2561620555 title "77. Antigen-Specific Modulation of Capsid Immunogenicity with Tolerogenic Nanoparticles Results in Successful AAV Vector Readministration" @default.
• W2561620555 doi "https://doi.org/10.1016/s1525-0016(16)32886-6" @default.
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