Aβ-directed Single-chain Antibody Delivery Via a Serotype-1 AAV Vector Improves Learning Behavior and Pathology in Alzheimer's Disease Mice

• Published in: Molecular therapy Vol. 18; no. 8; pp. 1471 - 1481
• Main Authors: Ryan, Deborah A, Mastrangelo, Michael A, Narrow, Wade C, Sullivan, Mark A, Federoff, Howard J, Bowers, William J
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-08-2010; Nature Publishing Group
• Subjects: Original
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2010.111

Alzheimer's disease (AD) is a progressive dementing disorder characterized by age-related amyloid-beta (Aβ) deposition, neurofibrillary tangles, and synapse and neuronal loss. It is widely recognized that Aβ is a principal pathogenic mediator of AD. Our goal was to develop an immunotherapeutic approach, which would specifically lead to the clearance and/or neutralization of Aβ in the triple transgenic mouse model (3xTg-AD). These mice develop the amyloid and tangle pathologies and synaptic dysfunction reminiscent of human AD. Using a human single-chain variable fragment (scFv) antibody phage display library, a novel scFv antibody specific to Aβ was isolated, its activity characterized in vitro, and its open reading frame subsequently cloned into a recombinant adeno-associated virus (rAAV) vector. Three-month-old 3xTg-AD mice were intrahippocampally infused with serotype-1 rAAV vectors encoding Aβ-scFv or a control vector using convection-enhanced delivery (CED). Mice receiving rAAV1-Aβ-scFv harbored lower levels of insoluble Aβ and hyperphosphorylated tau, and exhibited improved cognitive function as measured by the Morris Water Maze (MWM) spatial memory task. These results underscore the potential of gene-based passive vaccination for AD, and provide further rationale for the development of Aβ-targeting strategies for this debilitating disease.