TY - JOUR
T1 - AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy
AU - Ising, Christina
AU - Gallardo, Gilbert
AU - Leyns, Cheryl E.G.
AU - Wong, Connie H.
AU - Jiang, Hong
AU - Stewart, Floy
AU - Koscal, Lauren J.
AU - Roh, Joseph
AU - Robinson, Grace O.
AU - Serrano, Javier Remolina
AU - Holtzman, David M.
N1 - Funding Information:
This work was supported by funding from the Deutsche Forschungsgemeinschaft (IS 299/1-1) to C. Ising; National Institutes of Health (NIH) grant K01 NS096719-01 and McDonnell Center for Cellular and Molecular Neurobiology grant to G. Gallardo; and from NIH grant AG04867801, Tau Consortium, the JPB Foundation, and C2N Diagnostics to D.M. Holtzman. In addition, this work was supported by The Hope Center Viral Vectors Core, The Hope Center Alafi Neuroimaging Lab, and an NIH Shared Instrumentation Grant (S10 RR027552) to Washington University School of Medicine. Immunofluorescence data acquisition with a Nikon A1Rsi microscope were performed in part through the use of the Washington University Center for Cellular Imaging. C. Ising, G. Gallardo, C.E.G. Leyns, H. Jiang, and D.M. Holtzman are listed as inventors on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics, LLC. C2N Diagnostics, LLC has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M. Holtzman is on the scientific advisory board of Neurophage and consults for Genentech, Eli Lilly, AbbVie, and AstraZeneca. The authors declare no additional competing financial interests. Author contributions: C. Ising, G. Gallardo, and D.M. Holtzman conceived the study; C. Ising, G. Gallardo, C.E.G. Leyns, C.H. Wong, H. Jiang, F. Stewart, L.J. Koscal, J. Roh, G.O. Robinson, and J.Remolina Serrano carried out the experiments; C. Ising, G. Gallardo, and D.M. Holtzman designed experiments and analyzed the data; C. Ising, G. Gallardo, and D.M. Holtzman wrote the manuscript with input from all other authors. All authors approved the manuscript.
Publisher Copyright:
© 2017 Ising et al.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our 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, we engineered single-chain 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, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.
AB - Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our 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, we engineered single-chain 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, our study provides a novel strategy for anti-tau immunotherapeutics that potentially limits a detrimental proinflammatory response.
UR - http://www.scopus.com/inward/record.url?scp=85021855424&partnerID=8YFLogxK
U2 - 10.1084/jem.20162125
DO - 10.1084/jem.20162125
M3 - Article
C2 - 28416651
AN - SCOPUS:85021855424
SN - 0022-1007
VL - 214
SP - 1227
EP - 1238
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -