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。这项R21可行性研究的目的是鉴定能够靶向脉络膜丛（CP）的肽，以便评估它们将药物输送到脉络膜丛或穿过CP进入脑脊液（CSF）的能力。该研究的解剖学和治疗原理源于对脑脊液的观察，脑脊液是血液和脑脊液之间结构独特的界面，作为迄今为止未被认识的局灶通道，可以将抗坏血酸等自然发生的药物输送到大脑，特别是进入脑脊液。因此，除了靶向CNS的药物外，CP靶向也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药物转运功能，(2)改变其分泌CSF的能力，或(3)调节其放入CSF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来挖掘能够靶向CP的肽库，而不是应用合理的设计来创建CP和CSF治疗的药物递送剂。具体而言，我们建议确定(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；(3)可以跨CP转运进入CSF的肽。在本项目结束时，我们将确定3类肽，它们能够特异性靶向脑脊液的血液（基底外侧）和脑脊液（根尖）界面，用于神经退行性疾病期间脑脊液和脑脊液靶向的药物输送到大脑。

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.