RT Journal Article
SR Electronic
T1 AAV mediated delivery of a novel anti-BACE1 VHH reduces Abeta in an Alzheimer’s disease mouse model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 698506
DO 10.1101/698506
A1 Melvin Y. Rincon
A1 Lujia Zhou
A1 Catherine Marneffe
A1 Iryna Voytyuk
A1 Yessica Wouters
A1 Maarten Dewilde
A1 Sandra I. Duqué
A1 Cécile Vincke
A1 Yona Levites
A1 Todd E. Golde
A1 Serge Muyldermans
A1 Bart De Strooper
A1 Matthew G. Holt
YR 2019
UL http://biorxiv.org/content/early/2019/07/13/698506.abstract
AB Single domain antibodies (VHH) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHH have not been widely used in the central nervous system (CNS), as it is hard to reach therapeutic levels, both because of their restricted blood-brain-barrier penetration and their apparent rapid clearance from the parenchyma. Here, we propose a gene transfer strategy based on adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS, ensuring continuous production at therapeutic levels. 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 them, VHH-B9, showed high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We then went on to demonstrate significant reductions in amyloid beta (Aβ) levels after AAV-based delivery of VHH-B9 into the CNS of a mouse model of cerebral amyloidosis. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.