Anti-Abeta single-chain antibody delivery via adeno-associated virus for treatment of Alzheimer's disease.
Immunization of mouse models of Alzheimer disease (AD) with amyloid-peptide (Abeta) reduces Abeta deposits and attenuates their memory and learning deficits. Recent clinical trials were halted due to meningoencephalitis, presumably induced by T cell mediated and/or Fc-mediated immune responses. Because injection of anti-Abeta F(ab')(2) antibodies also induces clearance of amyloid plaques in AD mouse models, we have tested a novel gene therapy modality where an adeno-associated virus (AAV) encoding anti-Abeta single-chain antibody (scFv) is injected into the corticohippocampal regions of AD mouse models. One year after injection, expression of scFv was readily detectable in the neurons of the hippocampus without discernible neurotoxicity. AD mouse models subjected to AAV injection had much less amyloid deposits at the injection sites than the mouse models subjected to PBS injection. Because the scFv lacks the Fc portion of the immunoglobulin molecule, this modality may be a feasible solution for AD without eliciting inflammation.
Fukuchi
Ken-ichiro
K
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, PO Box 1649, Peoria, IL 61656, USA. kfukuchi@uicomp.uic.edu
Tahara
Kazuki
K
Kim
Hong-Duck
HD
Maxwell
J Adam
JA
Lewis
Terry L
TL
Accavitti-Loper
Mary Ann
MA
Kim
Helen
H
Ponnazhagan
Selvarangan
S
Lalonde
Robert
R
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D019556:COS Cells; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002522:Chlorocebus aethiops; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D000906:Antibodies; D007141:Immunoglobulin Fc Fragments