Alzheimer's disease is a fatal, progressive brain disease that deteriorates memory and cognitive ability, often starting years before the first symptoms appear. It is the most common form of dementia and the only top 10 cause of death that has no cure, no means of prevention, and no disease-modifying treatments. In this proposal we suggest a combination of novel nanostructure assembly technique based on Flexible Nano Arrays (FNA) and universal non-self vaccine platform MultiTEP for the creation of an efficient AD vaccine targeting A? dimers. This vaccine would be able to discriminate between pathological and physiological as well as toxic and inert forms of A?. This becomes especially important in the light of new evidence suggesting the functional importance of A? in neuronal plasticity and defense against brain infections. Ability to target selectively highly toxic soluble forms of A? is also important, since generation of antibodies that bind to mostly inert, fibrillar forms of A? is suboptimal due to the possibility of solubilization of plaques and release of large amounts of toxic soluble A? oligomers. Also, targeting the fibrillary forms of A? may lead to increased activation of complement in the regions with vascular amyloid deposits and induce additional adverse effects associated with vascular inflammation. The oligomeric forms of A? are highly neurotoxic and should be the primary target in AD immunotherapy, yet their structure is not well-defined and is mostly predicted based on the knowledge about the structure of fibrillar A?. Synthetic oligomeric forms of A? are transient and heterogeneous in size, therefore we hypothesize that a successful immunotherapy approach for AD needs well-defined antigens. The objective of this proposal is to develop an approach by which a flexible nanoarray will be utilized to assemble dimers of A?14-23 peptide and conjugate them with the universal and immunogenic MultiTEP platform to generate a novel vaccine targeting dimeric A?, which is considered to be a seed for the generation of other toxic forms of A?. The immunogenic efficacy and specificity of the vaccine will be tested in vivo allowing us to optimize the vaccine assembly methodology. We hypothesize that (a) combining conformational B cell epitope/s exposed on A?14-23 dimers with MultiTEP platform (dA?-MultiTEP) will allow us to generate an effective vaccine, which, after formulation in proprietary Advax/CpG adjuvant, will overcome immunogenicity limitation even in elderly people with immunosenescence; (b) dimer-specific antibodies will not only be therapeutically effective, but also safe, due to the absence of adverse events associated with solubilization of plaques and clearance of monomeric A?.

Public Health Relevance

We suggest combining novel Flexible NanoArrays (FNA) polymer based assembly of loosely organized nanostructures with the universal non-self Th epitope based vaccine platform MultiTEP to create efficient vaccines against Alzheimer's Disease, targeting A? dimers, which are the earliest event in the formation of toxic soluble oligomers. The creation of an active vaccine against this promising novel target would address the lack of antigenic determinants, which can efficiently discriminate between pathological and physiological as well as toxic and inert forms of A?. We hypothesize that such a vaccine will be highly immunogenic, will overcome immunogenicity limitation even in elderly people with immunosenescence, and will induce dimer- specific antibodies that will not only be therapeutically effective, but also safe, due to the absence of side effects associated with the solubilization of plaques and clearance of monomeric A?.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS101504-02
Application #
9431257
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Corriveau, Roderick A
Project Start
2017-02-15
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Institute for Molecular Medicine
Department
Type
DUNS #
957283229
City
Huntington Beach
State
CA
Country
United States
Zip Code
92647