Alzheimer disease (AD) is the most common neurodegenerative disease in the elderly. To date, no satisfactory treatment is available for AD. One of the pathological hallmarks of AD is deposits of amyloid protein (A?) in neuritic plaques and cerebral vessels. Increasing lines of evidence support the notion that A? and its precursor (APP) play pathogenetic roles in the etiology of AD. Overexpression of the mutant forms of APP in transgenic mice led to AD-like pathologies including amyloid plaques in the brain. Parenteral immunization of these AD mouse models with synthetic A? prevented or reduced A? deposits and improved their memory and learning deficits. Human clinical trials of A? immunization, however, were halted due to brain inflammation presumably induced by T cell-mediated autoimmune responses. Recent reports of the clinical trials indicate that A? immunization is effective in clearing A? deposits and improving cognitive deficits in AD patients. Thus, it is crucial to find safe and effective immune therapy. Peripheral administration of antibodies against A? also induced clearance of preexisting amyloid plaques in AD mouse models. Therefore, the development of successful therapeutic vaccines against AD is thought to depend on identification of immunization strategies that can induce potent A?-specific Th2 immune responses without eliciting adverse effects. We produced an adenovirus-vectored vaccine which encodes a B-cell epitope of A?. The adenovirus vaccine induced predominantly Th2 immune responses and had prophylactic effects on AD-like changes in AD model mice. Vaxin Inc. developed the proprietary AdHigh system for rapid production of replication-competent adenovirus (RCA)-free adenovirus vectors. Based upon our experimental results, we will further assess the safety and efficacy of the RCA-free adenovirus vector in treating AD model mice in the Phase I project.
The Specific Aims are (1) Construction of the RCA-free adenovirus vector, (2) Determination of immune responses induced by nasal administration of the RCA-free adenovirus vector in an AD mouse model, and (3) Evaluation of the efficacy and the safety of the nasal administration of the RCA-free adenovirus vector in an AD mouse model. Therefore, this application is a necessary step toward a clinical trial of our adenovirus vectored vaccine. Primer's disease (AD) is characterized by the progressive loss of memory and cognitive functions. To date, no satisfactory treatments are available for AD. We propose to test the efficacy and safety of a RCA-free adenovirus vectored vaccine using animal models of AD in order to treat and prevent AD. ? ? ?
