Neuroscience Discovery, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Large Molecule Research, Roche Pharma Research and Early Development, Roche Innovation Center Munich, Munich, Germany.
PLoS One. 2020 Mar 10;15(3):e0229850. doi: 10.1371/journal.pone.0229850. eCollection 2020.
Reducing Amyloid β (Aβ) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer`s disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key Aβ-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central Aβ. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading Aβ in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial Aβ reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an Aβ degrading enzyme across the blood-brain barriers to efficiently reduce Aβ levels in both CSF and brain.
降低大脑中的淀粉样蛋白β（Aβ）对于推进阿尔茨海默病的治疗方法至关重要。内源性金属肽酶 Neprilysin（NEP）已被确定为 Aβ 降解酶之一。利用 Brain Shuttle（BS）转运系统将 NEP 递送到大脑，为清除中枢 Aβ 提供了一种很有前途的方法。我们将 NEP 的细胞外催化结构域融合到活性或非活性的 BS 模块上。使用这两种 BS-NEP 构建体来研究剂量反应和多次给药时血液和脑脊液（CSF）中的药代动力学/药效学关系。如前所述，NEP 在外周给药后可有效降解血液中的 Aβ，但不能降解 CSF 中的 Aβ。相比之下，具有活性 BS 模块的 NEP 导致 BS-NEP 在 CSF 中显著暴露，随后 CSF 和脑实质中的 Aβ 显著减少。我们的数据表明，针对转铁蛋白受体的 BS 模块可促进 Aβ 降解酶穿过血脑屏障，从而有效降低 CSF 和脑实质中的 Aβ 水平。
