P2-355: Trimer Aβ42 gene vaccine elicits a high level of antibody production when delivered with the GAL4-UAS system and the gene gun

Amyloid β 42 (Aβ42) gene vaccination is a potential therapy for prevention and treatment of Alzheimer's disease. A key concern in this approach is the need for high level antibody response without inducing CTL against Aβ. Using the gene gun mediated delivery method, we demonstrate that the binary Gal4/UAS system encoding the trimer Aβ42 gene (3 copies of the Aβ42 cDNA) may meet this criteria, eliciting a high level of antibody production in vivo against Aβ42. The Gal4/UAS system consists of an activator construct that expresses a yeast transcription factor, Gal4, and an effector construct that contains DNA-binding motifs for Gal4 (UAS) linked to the trimer Aβ42 gene. Co-shooting of these two plasmids into the mouse ear skin with the gene gun elicits high anti-Aβ42 antibody production, 10- 25 μg/ml compared to 2 to 6 μg/ml with Aβ42 monomer constructs. The serotype ratio is approximately 2:1 (IgG1:IgG2a). Importantly, no significant cytotoxic T cell response is elicited as tested by the ELISPOT assay for gamma interferon levels in mouse spleen T cells. In vitro transfection of the human cell line HEK293 shows higher Aβ42 peptide production with the trimer construct compared to the monomer Aβ42 construct. We believe that more antigen (Aβ42) production is the reason for an increased level of antibody production with the trimer Aβ42 construct compared to the Aβ42 monomer construct. These high titers of anti-Aβ42 antibody elicited by the trimer Aβ42 construct provide levels of anti-Aβ42 antibody that offer potential therapy for Alzheimer's disease.