Marino, Marika;
Zhou, Lujia;
Rincon, Melvin Y;
Callaerts-Vegh, Zsuzsanna;
Verhaert, Jens;
Wahis, Jérôme;
Creemers, Eline;
... Holt, Matthew G; + view all
(2022)
AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.
EMBO Molecular Medicine
, 14
(4)
, Article e09824. 10.15252/emmm.201809824.
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Abstract
Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood–brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the AppNL-G-F Alzheimer’s mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.
| Type: | Article |
|---|---|
| Title: | AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.201809824 |
| Publisher version: | https://doi.org/10.15252/emmm.201809824 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | AAV, Alzheimer’s disease, VHH, anti-BACE1 |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10146616 |
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