Meng Yu, Wiseman Jennifer A, Nemtsova Yuliya, Moore Dirk F, Guevarra Jenieve, Reuhl Kenneth, Banks William A, Daneman Richard, Sleat David E, Lobel Peter
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Wenzhou-Kean University, Wenzhou, Zhejiang 32050, China.
Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Mol Ther. 2017 Jul 5;25(7):1531-1543. doi: 10.1016/j.ymthe.2017.03.037. Epub 2017 Apr 26.
We have investigated delivery of protein therapeutics from the bloodstream into the brain using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a lysosomal disease due to deficiencies in tripeptidyl peptidase 1 (TPP1). Supraphysiological levels of TPP1 are delivered to the mouse brain by acute intravenous injection when co-administered with K16ApoE, a peptide that in trans mediates passage across the blood-brain barrier (BBB). Chronic treatment of LINCL mice with TPP1 and K16ApoE extended the lifespan from 126 to >294 days, diminished pathology, and slowed locomotor dysfunction. K16ApoE enhanced uptake of a fixable biotin tracer by brain endothelial cells in a dose-dependent manner, suggesting that its mechanism involves stimulation of endocytosis. Pharmacokinetic experiments indicated that K16ApoE functions without disrupting the BBB, with minimal effects on overall clearance or uptake by the liver and kidney. K16ApoE has a narrow therapeutic index, with toxicity manifested as lethargy and/or death in mice. To address this, we evaluated variant peptides but found that efficacy and toxicity are associated, suggesting that desired and adverse effects are mechanistically related. Toxicity currently precludes direct clinical application of peptide-mediated delivery in its present form but it remains a useful approach to proof-of-principle studies for biologic therapies to the brain in animal models.
我们利用晚发性婴儿神经元蜡样脂褐质沉积症（LINCL）小鼠模型研究了蛋白质治疗药物从血流进入大脑的情况。LINCL是一种溶酶体疾病，由三肽基肽酶1（TPP1）缺乏引起。当与K16ApoE共同急性静脉注射时，超生理水平的TPP1被递送至小鼠大脑，K16ApoE是一种能介导跨血脑屏障（BBB）转运的肽。用TPP1和K16ApoE对LINCL小鼠进行长期治疗，可将其寿命从126天延长至>294天，减轻病理变化，并减缓运动功能障碍。K16ApoE以剂量依赖的方式增强脑内皮细胞对可固定生物素示踪剂的摄取，表明其作用机制涉及刺激内吞作用。药代动力学实验表明，K16ApoE在不破坏血脑屏障的情况下发挥作用，对肝脏和肾脏的总体清除率或摄取影响最小。K16ApoE的治疗指数较窄，在小鼠中表现出嗜睡和/或死亡等毒性。为了解决这个问题，我们评估了变体肽，但发现疗效和毒性相关，这表明预期效应和不良反应在机制上相关。目前，毒性妨碍了肽介导递送以其目前形式直接应用于临床，但它仍然是动物模型中脑生物治疗原理验证研究的一种有用方法。
