Targeting the choroid plexus for drug translocation into CSF

描述(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制药输送到中枢神经系统，用于中风治疗和神经退行性疾病的治疗。这一探索性的R21可行性研究方案的目标是识别能够靶向脉络丛(CP)的多肽，以便评估它们向CP或通过CP进入脑脊液(CSF)的药物输送能力。这项拟议研究的解剖学和治疗学基础源于这样一个观察，即CP是血液和脑脊液之间在结构上独特的界面，充当迄今未被识别的焦点通道，可以将自然产生的抗坏血酸等物质输送到大脑，特别是脑脊液。因此，除了以中枢神经系统为靶点的药物外，CP靶向还将开启创造新的基于CP的神经疗法的可能性，这些疗法可以(1)直接改变CP的药物转运功能，(2)改变其分泌脑脊液的能力，或(3)调节其植入脑脊液的因子(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，为那些能够靶向CP的人挖掘多肽库，而不是应用合理的设计来创造用于CP和CSF治疗的药物递送剂。具体地说，我们建议识别(1)靶向CP内皮细胞和基质细胞的多肽(2)靶向CP上皮细胞的多肽，以及(3)可跨CP转位进入脑脊液的多肽。在本项目结束时，我们将确定三类能够针对CP的血液(基侧)和脑脊液(心尖)界面特异性靶向CP和CSF的多肽-在神经退行性疾病期间靶向向大脑输送药物。

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.