AAV‐mediated delivery of an anti‐BACE1 VHH alleviates pathology in an Alzheimer’s disease model

Abstract

AbstractBackgroundSingle 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), largely because of their restricted blood‐brain barrier (BBB) penetration. To overcome this restriction, we designed a gene transfer strategy using 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, given its well‐characterized and central role in Alzheimer’s disease.MethodIn a first step, we generated a panel of novel VHHs targeting BACE1: one of these, VHH‐B9, demonstrates high selectivity for BACE1 and appears to specifically inhibit APP‐cleavage in vitro. On the basis that a substrate‐selective inhibition of BACE1 may overcome the mechanism‐based adverse effects commonly reported in BACE1 inhibitor trials, we selected VHH‐B9 for incorporation into a BBB‐crossing vector.ResultA 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, without any overt signs of toxicity.ConclusionThese results suggest that long‐term BACE1 inhibition, with a selective APP‐cleavage inhibitor, may constitute a novel therapeutic approach for Alzheimer’s disease. More broadly, we propose that AAV‐mediated VHH delivery will be a useful tool for the treatment of a range of CNS disorders.