A Therapeutic DNA Epitope Vaccine for Alzheimer's Disease

点击翻译按钮获取中文摘要

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is estimated that there are currently more than 18 million people worldwide with AD and this number is projected to nearly double by 2025 to 34 million. The enormous, increasing worldwide healthcare burden of AD and the lack of effective drugs indicate new prophylactic and/or therapeutic approaches for treating AD are essential. One neuropathological feature of the disease is the presence of plaques composed primarily of a peptide called b- amyloid (A?). Currently, the predominant theory of the etiology of AD is that A? has a central role in the onset and progression of AD. According to this hypothesis, the accumulation of A? peptide, either by overproduction or aberrant clearance, results in the deposition of A? in plaques, which promotes the formation of neurofibrillary tangles and cell death, resulting in dementia. Many strategies for the development of therapies for AD are aimed at reducing the level of A? in the brain and/or blocking assembly of the peptide into pathological forms that disrupt cognitive function. A variety of approaches based on active (i.e., vaccines) or passive (i.e., monoclonal antibodies) immunotherapy against A? have demonstrated the capability to alter A? plaque burden in disease models and early phase clinical trials. The most advanced clinical trial evaluated an A? peptide vaccine (AN1792) developed by Elan Pharmaceuticals. Although a reduction in AD-related cognitive decline was observed in some of the immunized subjects, the trial was halted prematurely due to the occurrence of neuroinflammation in a subset of vaccine recipients. Subsequent analysis implicated the induction of autoreactive T cell responses to the A? peptide (but not antibody responses) in the development of these adverse events. Based on these findings, an A? B cell epitope DNA vaccine, ADepVac, was designed to elicit potent antibody responses to A? while avoiding the development of autoreactive T-cells. This candidate has demonstrated compelling safety and efficacy characteristics in AD murine disease models and strong synergy with electroporation-based DNA delivery technology. To evaluate the long term potential of this product as an intervention for AD, Ichor and its collaborators propose that the objective of SBIR U44 Phase I will be to verify that ADepVac can safely and effectively induce target levels of immune responses in non-human primates when delivered with electroporation-mediated delivery. If the safety and performance feasibility criteria are achieved, U44 Phase II will be initiated in order to complete the nonclinical safety/toxicological studies and regulatory filings necessary to support the initiation of a Phase I clinical trial in humans. Based on the diverse, interdisciplinary expertise assembled among the program collaborators, the project is well positioned to bring ADepVac into clinical testing.