@article{66397433e99941c784d75a8202e6efeb,
title = "Gene therapy using Aβ variants for amyloid reduction",
abstract = "Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid β (Aβ) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aβ variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases.",
keywords = "APP/PS1 mouse, P0 injection, amyloid, peptide inhibitor, viral vector",
author = "Park, {Kyung Won} and Wood, {Caleb A.} and Jun Li and Taylor, {Bethany C.} and Oh, {Sae Woong} and Young, {Nicolas L.} and Jankowsky, {Joanna L.}",
note = "Funding Information: We thank Kazu Oka and the BCM Gene Vector Core for viral packaging. Thioflavin-T assays were read at the BCM Center for Drug Development. Meso Scale Discovery assays were read at The University of Texas Health Science Center Quantitative Genomics and Microarray Service Center. The graphical abstract was created with BioRender (BioRender.com). This work was supported by NIH R01 NS092615, RF1 AG054160, RF1 AG058188, and R21 AG056028 and the Robert A. and Renee E. Belfer Family Foundation to J.L.J. and NIH R01 GM139295 to N.L.Y. K.-W.P. and J.L.J. designed the study and wrote the manuscript with input from other authors. K.-W.P. C.A.W. J.L. and S.O. performed in vitro and in vivo experiments and analyzed the data. B.C.T. and N.L.Y. designed, performed, and analyzed the mass spectrometry experiments. K.-W.P. completed the bulk of this study while employed at Baylor College of Medicine performing work that was fully funded by NIH and a non-profit research foundation. In July 2020, K.-W.P. left Baylor to become CEO of Aβrain, a biotechnology company he founded to pursue AAV-based therapeutics for protein aggregation disorders. He is currently a paid employee and sole owner of Aβrain. The other authors declare no competing interests. Funding Information: K.-W.P. completed the bulk of this study while employed at Baylor College of Medicine performing work that was fully funded by NIH and a non-profit research foundation. In July 2020, K.-W.P. left Baylor to become CEO of Aβrain, a biotechnology company he founded to pursue AAV-based therapeutics for protein aggregation disorders. He is currently a paid employee and sole owner of Aβrain. The other authors declare no competing interests. Funding Information: We thank Kazu Oka and the BCM Gene Vector Core for viral packaging. Thioflavin-T assays were read at the BCM Center for Drug Development. Meso Scale Discovery assays were read at The University of Texas Health Science Center Quantitative Genomics and Microarray Service Center. The graphical abstract was created with BioRender ( BioRender.com ). This work was supported by NIH R01 NS092615 , RF1 AG054160 , RF1 AG058188 , and R21 AG056028 and the Robert A. and Renee E. Belfer Family Foundation to J.L.J. and NIH R01 GM139295 to N.L.Y. Publisher Copyright: {\textcopyright} 2021 The American Society of Gene and Cell Therapy",
year = "2021",
month = jul,
day = "7",
doi = "10.1016/j.ymthe.2021.02.026",
language = "English (US)",
volume = "29",
pages = "2294--2307",
journal = "Molecular therapy : the journal of the American Society of Gene Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "7",
}