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• W2042037138 abstract "Hepatocytes are an effective depot for protein production from gene therapy vectors. However, when gene transfer vectors or their delivery induces hepatic inflammation, adaptive immune responses against the transgene product can ensue. In BALB/c mice, hydrodynamic delivery of a CMV-driven plasmid DNA (pDNA) bearing human α-galactosidase A (αgal) to the liver generated antibodies against αgal. This humoral immune response was more robust in a transgenic knockout for αgal, the Fabry mouse. The antibody response could be attenuated in both mouse strains by using a promoter more restricted to hepatocytes. In an attempt to reduce further the humoral responses to αgal, expression from the transgene was attenuated by using siRNA during the period of initial delivery-associated liver inflammation. In both mouse models and with both promoters, codelivering an αgal siRNA resulted in a 2 log decrease in initial expression that then increased over the next few weeks to levels generated by the pDNA alone. This strategy led to both attenuated antibodies and an immune status approximating “tolerance” to αgal. Importantly, in the Fabry mouse, an αgal siRNA together with a hepatocyte-restricted promoter gave minimal anti-αgal antibodies and profound tolerance, suggesting that such an approach might have clinical utility for genetic diseases." @default.
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• W2042037138 date "2005-08-01" @default.
• W2042037138 modified "2023-10-16" @default.
• W2042037138 title "Transient siRNA-Mediated Attenuation of Liver Expression from an α-Galactosidase a Plasmid Reduces Subsequent Humoral Immune Responses to the Transgene Product in Mice" @default.
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• W2042037138 doi "https://doi.org/10.1016/j.ymthe.2005.04.007" @default.
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