Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
Mol Ther. 2020 Oct 7;28(10):2161-2176. doi: 10.1016/j.ymthe.2020.06.011. Epub 2020 Jun 15.
During brain maturation, cation-independent mannose-6-phosphate receptor (CI-MPR), a key transporter for lysosomal hydrolases, decreases significantly on the blood-brain barrier (BBB). Such a phenomenon leads to poor brain penetration of therapeutic enzymes and subsequent failure in reversing neurological complications in patients with neuropathic lysosomal storage diseases (nLSDs), such as Hurler syndrome (severe form of mucopolysaccharidosis type I [MPS I]). In this study, we discover that upregulation of microRNA-143 (miR-143) contributes to the decline of CI-MPR on the BBB during development. Gain- and loss-of-function studies showed that miR-143 inhibits CI-MPR expression and its transport function in human endothelial cells in vitro. Genetic removal of miR-143 in MPS I mice enhances CI-MPR expression and improves enzyme transport across the BBB, leading to brain metabolic correction, pathology normalization, and correction of neurological functional deficits 5 months after peripheral protein delivery at clinically relevant levels that derived from erythroid/megakaryocytic cells via hematopoietic stem cell-mediated gene therapy, when otherwise no improvement was observed in MPS I mice at a parallel setting. These studies not only uncover a novel role of miR-143 as an important modulator for the developmental decline of CI-MPR on the BBB, but they also demonstrate the functional significance of depleting miR-143 for "rescuing" BBB-anchored CI-MPR on advancing CNS treatment for nLSDs.
在大脑成熟过程中，溶酶体水解酶的关键转运蛋白阳离子非依赖性甘露糖-6-磷酸受体（CI-MPR）在血脑屏障（BBB）上显著减少。这种现象导致治疗性酶在大脑中的穿透性差，随后无法逆转神经病变性溶酶体贮积病（nLSD）患者的神经并发症，如 Hurler 综合征（I 型黏多糖贮积症的严重形式[MPS I]）。在这项研究中，我们发现 microRNA-143（miR-143）的上调导致 CI-MPR 在发育过程中在 BBB 上的下降。增益和失能研究表明，miR-143 在体外抑制人内皮细胞中的 CI-MPR 表达及其转运功能。在 MPS I 小鼠中遗传去除 miR-143 可增强 CI-MPR 的表达，并改善酶穿过 BBB 的转运，导致脑代谢纠正、病理学正常化以及在以临床相关水平通过造血干细胞介导的基因治疗从红系/巨核细胞衍生的外周蛋白给药后 5 个月纠正神经功能缺陷，而在平行设置中，MPS I 小鼠则没有观察到任何改善。这些研究不仅揭示了 miR-143 作为 BBB 上 CI-MPR 发育性下降的重要调节剂的新作用，而且还证明了耗竭 miR-143 对于“挽救”进展性中枢神经系统治疗 nLSD 中 BBB 锚定的 CI-MPR 的功能意义。
