761. Genotoxicity Free Intranasal Gene Vaccines for Alzheimer's Disease and AIDS with Remarkable Efficacy in Model Animals; Use of a Cytoplasmic RNA Vector, Sendai Virus Vectors

Top of pageAbstract The cytoplasmic RNA vector would be promising for use in gene vaccines to large population of patients or infected persons in urgent or in hospitals of various conditions because of its important genotoxicity-free nature. The candidate intranasal gene vaccines have been developed using Sendai virus (SeV) vector for both infectious and neurodegenerative diseases such as AIDS and Alzheimer's disease (AD), respectively. SeV belonging to the Genus Respirovirus, infects and multiplies its genome copy in most mammalian cells. Its replication is strictly in cytoplasm and independent of nuclear functions of host cells. Moreover, SeV does not have a DNA phase during its life cycle, so SeV-based vectors that express high-level of transgene do not need to be concerned about the transformation of cells by integration of vector materials into the host chromosomes. These properties of the vector enable us to propose the new concepts, CYTOPLASMIC GENE THERAPY and CYTOPLASMIC VACCINATION with RNP-based treatment. For the treatment of AD, the F gene-deleted non-transmissible SeV (SeV/|[Delta]|F) vector carrying amyloid-|[beta]| (A|[beta]|) gene was used. According to the |[ldquo]|Amyloid Cascade Theory|[rdquo]|, the formation of senile plaques through aggregation and deposition of A|[beta]| peptides in the brain is considered as a major cause of the disease. Thus, immune-mediated strategy known as A|[beta]| vaccination has been thought to be a promising therapeutic approach for the treatment of Alzheimer's disease. Single intranasal administration of SeV vector carrying A|[beta]| gene (A|[beta]| 1|[ndash]|43) to the 24 to 25-month-old APP transgenic mice induced the expression of the A|[beta]| peptide in the epithelial cells of the nasal mucosa. Serum antibody level was elevated and the amyloid burdens in the brain were decreased to 10|[ndash]|20% of the control mice after eight weeks treatment. Importantly, no lymphocytes infiltration that into the central nervous system was detected. For the AIDS vaccine, the Gag-expressing SeV/|[Delta]|F vector was used. Macaques vaccinated with DNA-prime/Gag-expressing SeV/|[Delta]|F-boost were challenged intravenously with the pathogenic simian immunodeficiency virus (SIVmac239) that induces chronic disease progression. The SeV boost induced Gag-specific CD4+ T cells, and its level in peripheral T lymphocytes was maintained for more than 40 weeks. The vaccine-induced cytotoxic T lymphocytes (CTLs) controlled SIVmac239 replication well. Thus, the mucosal immunotherapy with SeV vector has the great potential of prevention and treatment for both infectious and neurodegenerative diseases and might be a novel, attractive approach in gene vaccines of coming age.