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PNAS：跨越血脑屏障 带来治疗的新革命 |
| 作者： 来源：生物谷 时间： 2007-05-16
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生物谷报道：血脑屏障一直是许多中枢系统疾病治疗的重要难点，许多药物都因为无法在脑内形成有效的血药浓度，从而使治疗效果大大下降。
刚刚在本期PNAS上，以色列科学家Vivian I. Teichberg发现一种全新的方法，使透过血脑屏障变得简单，这一方法如何大规模应用，将开创中枢神经系统疾病治疗的革命，尤其是象蛋白质类的大分子。研究表明，在血脑屏障上有一些受体，如果某些蛋白质能很好地与这些受体结合，那么就容易被输入到中枢神经系统内。因此，以色列科学家便寻找一种能与血脑屏障上受体结合的新的治疗手段。作用使用慢病毒（lentivirus)载体系统，将溶酶体的一种酶---β-葡萄糖脑苷脂酶(β-glucocerebrosidase)和分泌状态的GFP制成融合蛋白，发现能成功在肝脏和脑中得到表达。进一步，再融合了低密度脂蛋白受体结合域到此蛋白，进一步促进了蛋白透过血脑屏障进入大脑。为此，PNAS专门为此文发表了相关的评论，高度评价了，这一治疗方法的重要意义与价值。
以下是目前所有的穿透血脑屏障的已有的方法的比较：
Table 1. Methods used to deliver drugs across the BBB
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Strategy
Method (representative refs.)
Major drawback
Neurosurgical approach
Injection within the CSF (3, 12)
Limited diffusion
i.c.v. administration (13)
Limited diffusion
Drug-releasing implants (5)
Local delivery
Peritumoral infusion (14)
Invasive
Chemical approach
Liposome and nanoparticle encapsulation (15)
Enter all organs
Cationization (6, 13)
Enter all organs
BBB opening
Intracarotid injection of hyperosmotic fluid (7)
Transient opening
BBB bypass
Intranasal delivery (8)
Limited size of <10 kDa, limited concentration
Cell therapy
Stem cell differentiation and engrafment in the CNS (16)
Low yield
Gene therapy
Receptor-mediated transcytosis of liposome-encapsulated RNAi and DNA (17)
Repeated injection
Viral vectors (18)
Invasive, limited diffusion
Protein therapy
Protein overload (19)
Low yield
Receptor-mediated transcytosis (9, 11)
Immunoreactivity |
i.c.v., intracerebroventricular.
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这是PNAS对此文的评价：
Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood–brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood–brain barrier bind ligands to facilitate their transport to the CNS; therefore, we hypothesized that by targeting these receptors, we may be able to deliver proteins to the CNS for therapy. Here, we report the use of the lentivirus vector system to deliver the lysosomal enzyme glucocerebrosidase and a secreted form of GFP to the neurons and astrocytes in the CNS. We fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to the targeted protein. This approach proved to be feasible for delivery of the protein and could possibly be used as a general method for delivery of therapeutic proteins to the CNS.
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