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P3‐442: Preclinical and early clinical studies of AVN‐101, a novel balanced molecule for the treatment of Alzheimer's disease
Author(s) -
Lavrovsky Yan,
Ivachtchenko Alexander V.,
Morozova M.,
Salimov R.M.,
Kasey V.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1984
Subject(s) - in vivo , safety pharmacology , pharmacology , medicine , radioligand , pharmacokinetics , clinical trial , disease , adme , neuroscience , drug , receptor , psychology , biology , microbiology and biotechnology
to reduce the potential toxicity of an immune response to a normal self protein. Methods: We used active immunization with aggregated British amyloid (ABri) related peptides in a predominantly b-sheet conformation alone or in combination with related immunogens. ABri is a rare form of familial human amyloidosis associated with a mis-sense mutation in a stop codon resulting in the production of a highly amyloidogenic protein with no sequence homology to other native human proteins. This immunization was done in APP/PS1 Tg mice, vascular amyloid model Tg SwDI mice and in 3x Tg mice with both tau and amyloid pathology Results: Our preliminary data indicates that mice immunized with aggregated/oligomerized preparations of ABri recognized heterologous amyloid structures including oligomeric Ab and PrP. ABri has no sequence homology with Ab, tau or PrP; hence, this immune response is not amino acid sequence specific but represents a preferential targeting of the pathological protein/peptide conformations shared by Ab, tau and PrP. Immunization of APP/PS1 AD Tg and the TgSwDI mice with ABri produces significant cognitive benefits in association with marked reductions in the parenchymal and vascular amyloid burdens, as well as reduced Ab oligomer levels, in the absence of any evident toxicity. Conclusions: Our results suggest that conformationally based immunomodulation targeting the pathological conformational mimicry of multiple disease associated proteins is feasible and effective.