VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
Department of Neurosciences, KU Leuven, Leuven, Belgium.
EMBO Mol Med. 2022 Apr 7;14(4):e09824. doi: 10.15252/emmm.201809824. Epub 2022 Mar 30.
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 Alzheimer's mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.
单域抗体（VHH）是一种具有潜在颠覆性的治疗药物，对于治疗包括神经紊乱在内的多种疾病具有重要的生物学价值。然而，VHH 尚未在中枢神经系统（CNS）中广泛应用，主要是因为其对血脑屏障（BBB）的穿透性有限。在这里，我们提出了一种基于 BBB 穿透型腺相关病毒（AAV）载体的基因转移策略，旨在将 VHH 直接递送至 CNS。作为概念验证，我们探索了 AAV 递送的 VHH 抑制 BACE1 的潜力，BACE1 是阿尔茨海默病的一个特征明确的靶点。首先，我们生成了一组针对 BACE1 的 VHH，其中一个 VHH-B9 对 BACE1 具有高选择性，在体外降低 BACE1 活性方面具有功效。我们进一步证明，单次系统给予 AAV-VHH-B9 可在 App 阿尔茨海默病小鼠模型中产生积极的长期（12 个月及以上）效果，包括降低淀粉样蛋白负荷、神经炎症、突触功能和认知表现。这些结果构成了一种治疗神经退行性疾病的新方法，适用于一系列 CNS 疾病靶点。
