Shire, Lexington, MA, USA.
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care Center, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Pharmacol Ther. 2014 Nov;144(2):114-22. doi: 10.1016/j.pharmthera.2014.05.009. Epub 2014 May 20.
Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world's leading causes of disability. Delivery of drugs to the CNS is complicated by the blood-brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood-brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally.
中枢神经系统（CNS）疾病，包括中风、神经退行性疾病和脑肿瘤，是全球致残的主要原因。药物向中枢神经系统的输送受到血脑屏障的阻碍，该屏障可防止血液中不受调节的物质（包括蛋白质）泄漏和进入大脑。然而，蛋白质是治疗 CNS 疾病最有前途的一类治疗药物之一。目前正在开发许多克服这些障碍的策略，但通过直接鞘内给药绕过这些障碍的相对简单方法在很大程度上被忽视了。由于其缺乏将小的脂溶性药物递送到大脑的用途，最初被排除在外，鞘内途径已成为某些治疗性蛋白质和靶向疾病组合的一种有用的、在某些情况下可能是理想的给药途径。在这里，我们综述了血脑屏障的功能和脑脊液动力学及其与鞘内途径药物输送的相关性，讨论了已经研究过鞘内递蛋白治疗药物的动物和人体研究，并概述了允许它们成功鞘内递的几种蛋白质治疗药物的特性。
