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AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy


Year of Publication:
Contact PI Name:
David M. Holtzman
Contact PI Affiliation:
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St. Louis, Missouri, USA
Christina Ising, Gilbert Gallardo, Cheryl E.G. Leyns, Connie H. Wong, Hong Jiang, Floy Stewart, Lauren J. Koscal, Joseph Roh, Grace O. Robinson, Javier Remolina Serrano
Primary Reference (PubMED ID):
Funding Source:
Deutsche Forschungsgemeinschaft/German Research Foundation
National Institute of Neurological Disorders and Stroke (NINDS)
McDonnell Center for Cellular and Molecular Neurobiology
National Institute on Aging (NIA)
Tau Consortium
JPB Foundation
C2N Diagnostics
The Hope Center Viral Vectors Core
The Hope Center Alafi Neuroimaging Lab
Study Goal and Principal Findings:

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. This laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the Fc domain of HJ8.5 is required for the therapeutic effect, single-chain was engineered, variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. Based on different binding properties, we selected two anti-tau scFvs and tested their efficacy in vivo by adeno-associated virus-mediated gene transfer to the brain of P301S-tg mice. The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in brain tissue of P301S-tg mice, associated with a decrease in detergent-soluble tau species. Interestingly, these mice showed substantial levels of scFvs in the cerebrospinal fluid without significant effects on total extracellular tau levels. Therefore, this study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
HJ8.5 Single Chain Variable Fragments (anti-Tau ScFvs)
Therapeutic Target:
Tau Protein

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Activated Microglia
Activated Astrocytes
Tau Pathology
Glial Fibrillary Acidic Protein (GFAP)
Soluble Tau
Insoluble Tau
Tau Uptake
CSF-Tau Protein
ISF-Tau Protein
Tau Seeding
Total Tau Protein
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Glial Fibrillary Acidic Protein (GFAP)
Tau Protein
Antibody Concentration-Plasma
Antibody Concentration-CSF
Antibody Concentration-Brain
Target Engagement (Reduction Tau)
Target Engagement (Reduction Tau-CSF)
Target Engagement (Binding to Tau Protein)