Targeting the choroid plexus for drug translocation into CSF

描述（由申请人提供）：为了充分利用从人类基因组测序中获得的知识，迫切需要将生物活性药物和生物药物递送到CNS中用于中风治疗和神经退行性疾病的治疗。这项探索性R21可行性研究提案的目标是鉴定能够靶向脉络丛（CP）的肽，以便评估它们将药物递送至CP或穿过CP进入脑脊液（CSF）的能力。所提出的研究的解剖学和治疗原理源于观察到CP是血液和CSF之间的结构上独特的界面，其充当迄今为止未被认识到的局灶性通道，其可以将天然存在的药剂如抗坏血酸递送到大脑中，特别是CSF中。因此，除了靶向CNS的药物之外，CP靶向还将开启创建新的基于CP的神经治疗剂的可能性，所述神经治疗剂（1）直接修饰CP药物转运功能，（2）改变其分泌CSF的能力或（3）调节其置于CSF中的因子（例如生长因子）的组成和浓度。然而，我们建议利用组合生物学和遗传选择的力量来挖掘能够靶向CP的肽库，而不是应用合理的设计来创建用于CP和CSF治疗的药物递送剂。具体而言，我们提出鉴定（1）靶向CP内皮细胞和基质细胞的肽，（2）靶向CP上皮细胞的肽，和（3）可以穿过CP并进入CSF的肽。在本项目结束时，我们将鉴定出3类肽，其能够特异性靶向CP的血液（基底外侧）和CSF（顶端）界面，用于在神经退行性疾病期间将药物递送至脑的CP和CSF靶向。

DESCRIPTION (provided by applicant): In order to fully exploit knowledge garnered from sequencing the human genome, there is a dire need to deliver biologically active drugs and biopharmaceuticals into the CNS for stroke therapies and the treatment of neurodegenerative disease. The goal of this exploratory R21 feasibility research proposal is to identify peptides capable of targeting the choroid plexus (CP) so that they can be evaluated for their capacity to deliver drugs to the CP or across the CP into cerebrospinal fluid (CSF). The anatomical and therapeutic rationale for the proposed research originates with the observation that the CP is a structurally unique interface between blood and CSF that acts as a heretofore unrecognized focal gateway that can deliver naturally occurring agents like ascorbic acid into the brain, and specifically into CSF. Accordingly, in addition to drug targeting the CNS, CP-targeting would also open the possibility of creating new CP-based neurotherapeutics that either (1) modify CP drug transport functions directly, (2) alter its capacity to secrete CSF or (3) modulate the composition and concentration of factors (e.g. growth factors) that it places into CSF. Rather then apply rational design to create drug delivery agents for CP and CSF therapeutics however, we propose to exploit the power of combinatorial biology and genetic selection to mine libraries of peptides for those capable of targeting CP. Specifically, we propose to identify (1) peptides that target CP endothelial and stromal cells (2) peptides that target CP epithelial cells and (3) peptides that can translocate across the CP and into CSF. At the conclusion of this project, we will have identified 3 classes of peptides capable of specifically targeting the blood (basolateral) and CSF (apical) interfaces of the CP for CP and CSF-targeted for drug delivery to the brain during neurodegeneratrive disease.