TY - JOUR
T1 - AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model
AU - Marino, Marika
AU - Zhou, Lujia
AU - Rincon, Melvin Y
AU - Callaerts-Vegh, Zsuzsanna
AU - Verhaert, Jens
AU - Wahis, Jérôme
AU - Creemers, Eline
AU - Yshii, Lidia
AU - Wierda, Keimpe
AU - Saito, Takashi
AU - Marneffe, Catherine
AU - Voytyuk, Iryna
AU - Wouters, Yessica
AU - Dewilde, Maarten
AU - Duqué, Sandra I
AU - Vincke, Cécile
AU - Levites, Yona
AU - Golde, Todd E
AU - Saido, Takaomi C
AU - Muyldermans, Serge
AU - Liston, Adrian
AU - De Strooper, Bart
AU - Holt, Matthew G
N1 - © 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - 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 disease mouse model. These results constitute a novel therapeutic approach forneurodegenerative diseases, which is applicable to a range of CNS disease targets.
AB - 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 disease mouse model. These results constitute a novel therapeutic approach forneurodegenerative diseases, which is applicable to a range of CNS disease targets.
UR - http://www.scopus.com/inward/record.url?scp=85127584902&partnerID=8YFLogxK
U2 - 10.15252/emmm.201809824
DO - 10.15252/emmm.201809824
M3 - Article
C2 - 35352880
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 4
M1 - e09824
ER -