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Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A.

To achieve efficient delivery and sustained expression of the human factor VIII cDNA in vivo, a minimal-adenoviral (mini-Ad) vector system was developed. The system is composed of a mini-Ad vector with essential cis-elements (less than 1 kb) of the viral genome, an E1-deleted ancillary Ad with packaging attenuation, and an E1-complementing production cell line. Based on this system, MiniAdFVIII was generated to deliver a 27 kb expression cassette consisting of a full-length human factor VIII cDNA flanked by human albumin promoter and genomic sequences. The MiniAdFVIII vector mediated expression of functional human factor VIII in HepG2 and 293 cells. A single-dose intravenous injection of 10(11) viral particles in hemophilic mice of MiniAdFVIII produced a sustained high-level expression of human factor VIII (at 100-800 ng/ml up to 369 days) which corrected the FVIII-deficient phenotype. Safety studies of MiniAdFVIII showed that there were no significant toxic effects in mice and dogs after single intravessel doses of up to 3 x 10(11) and 6 x 10(12) viral particles, respectively. Studies for developing the MiniAdFVIII vector with a site-specific integration mechanism and progress in the development of a human factor VIII-tolerized mouse model for pre-clinical studies of MiniAdFVIII are reported. Further pre-clinical studies and product development of MiniAdFVIII for clinical trials are also discussed.