Open AccessAAV‐mediated delivery of an anti‐BACE1 VHH alleviates pathology in an Alzheimer's disease model
Author(s) -
Marino Marika,
Zhou Lujia,
Rincon Melvin Y,
CallaertsVegh Zsuzsanna,
Verhaert Jens,
Wahis Jérôme,
Creemers Eline,
Yshii Lidia,
Wierda Keimpe,
Saito Takashi,
Marneffe Catherine,
Voytyuk Iryna,
Wouters Yessica,
Dewilde Maarten,
Duqué Sandra I,
Vincke Cécile,
Levites Yona,
Golde Todd E,
Saido Takaomi C,
Muyldermans Serge,
Liston Adrian,
De Strooper Bart,
Holt Matthew G
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809824
Subject(s) - neuroinflammation , single domain antibody , neuroscience , disease , amyloid (mycology) , central nervous system , in vivo , systemic administration , medicine , immunology , biology , antibody , pathology , microbiology and biotechnology
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 App NL‐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.