A Nanocarrier Platform for Targeting Schlemm's Canal Cells

用于靶向施累姆氏管细胞的纳米载体平台

基本信息

批准号：
10539739
负责人：
MARK JOHNSON
金额：
$ 55.7万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539739
关键词：
Actins Address Adverse effects Affect Animal Model Animals Antihypertensive Agents Aqueous Humor Attention Blood Vessels Bolus Infusion Cells Clinical Clinical Trials Cornea Corneal Endothelium Cytoskeleton Diagnostic Drug Carriers Drug Delivery Systems Drug vehicle Endothelial Cells Engineering Evaluation Exhibits Eye Formulation Frequencies Future Gene Delivery Glaucoma Histology Hour Human Hydrogels Hyperemia In Vitro Injectable Injections Measures Mechanics Micelles Microscopy Mind Modeling Monkeys Mus Ocular Hypotension Ophthalmoscopes Optical Coherence Tomography Pathway interactions Patients Perfusion Pharmaceutical Preparations Phenotype Physiologic Intraocular Pressure Plasmids Population Primary Open Angle Glaucoma Reducing Agents Reporter Resistance Resolution Retina Rho-associated kinase Specificity Structure of sinus venosus of sclera System Therapeutic Therapeutic Agents Therapeutic Effect Tissues Topical application Toxic effect Transfection Vascular Endothelial Cell Visible Radiation Work anterior chamber cellular targeting corneal epithelium depolymerization dosage efficacy evaluation eye chamber gene delivery system gene therapy in vivo kinase inhibitor latrunculin A mouse model nanocarrier nanoscale non-viral gene delivery nonhuman primate novel ocular hypotensive pressure rhoA GTP-Binding Protein side effect targeted delivery targeted treatment therapeutic target tonometry ultrasound uptake

项目摘要

PROJECT SUMMARY Nanoscale drug carriers (i.e. nanocarriers) have attracted much attention for their ability to transport diverse therapeutic and diagnostic agents and to selectively target specific cells and tissues. This increased specificity can have significant clinical implications, including decreased side effects and lower dosages with higher potency. Schlemm's canal (SC) endothelial cells hold promise as a cellular target for glaucoma therapy, as their mechanical stiffness is associated with modulation of intraocular pressure (IOP). Rho kinase inhibitors and actin- depolymerizing agents reduce endothelial cell stiffness and significantly lower IOP in animals and humans with several now approved for clinical use. However, these agents are associated with significant side effects, including conjunctival hyperemia and corneal verticillata. Studies show that >50% of patients treated with these therapeutics exhibit adverse side effects. Targeted nanocarrier delivery systems may address these issues but are not currently capable of passing through the corneal epithelium and must therefore be administered via intraocular injection. As frequent eye injections would not be well tolerated by patients, sustained intraocular delivery systems are needed to minimize the frequency of drug administration. Gene therapy targets for treatment of ocular hypotension have emerged, holding promise for a future glaucoma cure following a single intraocular injection, but a targeted gene delivery system is needed to enhance selective transfection of SC cells. A significant need therefore exists for both sustained nanocarrier delivery systems and gene delivery systems for intraocular strategies targeting the SC. With these needs in mind, the objective of this proposal is to engineer a scalable, customizable, synthetic nanocarrier platform that can be adapted to transport diverse therapeutic agents to outflow pathway cells with controllable release rates. Successful completion of this work will result in the first delivery system for sustained intraocular release of nanocarriers, a novel nonviral gene delivery platform for selective transfection of SC cells, and completion of nonhuman primate studies to justify clinical trials of these delivery systems in humans. The following Specific Aims will be completed: Aim 1: Optimize the duration of therapeutic effect for nanocarriers targeting Schlemm’s canal cells while avoiding side effects and toxicity within the cornea and vascular tissues in mouse eyes. Aim 2: Demonstrate nonviral transfection of Schlemm's canal cells in vivo using targeted nanocarriers without affecting nearby ocular tissues in mice Aim 3: Demonstrate that targeted nanocarriers containing latrunculin-A significantly increase conventional outflow facility and lower IOP in nonhuman primates without adverse effects.

项目概要纳米级药物载体（即纳米载体）因其运输多种药物的能力而备受关注。治疗和诊断剂并选择性地靶向特定细胞和组织，这增加了特异性。可以具有显着的临床意义，包括减少副作用和较低剂量施累姆氏管（SC）内皮细胞有望成为青光眼治疗的细胞靶点。机械硬度与眼压 (IOP) 的调节有关。解聚剂可降低动物和人类的内皮细胞硬度并显着降低眼压一些现已批准用于临床，但是这些药物具有显着的副作用，研究表明，>50% 的患者接受过这些治疗。靶向纳米载体递送系统可能会解决这些问题，但会产生不良副作用。目前无法穿过角膜上皮，因此必须通过由于患者不能很好地耐受频繁的眼部注射，因此需要持续进行眼内注射。需要递送系统来最大程度地减少基因治疗靶点的药物施用频率。低眼压的治疗方法已经出现，为未来青光眼的治愈带来了希望。眼内注射，但需要靶向基因递送系统来增强SC细胞的选择性转染。因此，对于持续的纳米载体递送系统和基因递送系统存在着巨大的需求考虑到这些需求，本提案的目标是设计针对 SC 的眼内策略。一个可扩展、可定制的合成纳米载体平台，可适应运输多种治疗药物药物以可控的释放速率流出途径细胞将成功完成这项工作。第一个持续眼内释放纳米载体的递送系统，一种新型非病毒基因递送平台用于选择性转染 SC 细胞，并完成非人灵长类动物研究以证明这些临床试验的合理性人类的输送系统。将完成以下具体目标：目标 1：优化纳米载体针对施累姆氏管细胞的治疗效果持续时间，同时避免对小鼠眼睛角膜和血管组织的副作用和毒性。目标 2：演示使用靶向纳米载体对施累姆氏管细胞进行体内非病毒转染，无需影响小鼠眼部组织附近目标 3：证明含有 latrunculin-A 的靶向纳米载体显着提高了常规纳米载体的在非人类灵长类动物中具有流出设施和较低的眼压，且无不良影响。