Sustained Delivery of RhoA activator for Treatment of Intervertebral Disc Degeneration

持续递送 RhoA 激活剂治疗椎间盘退变

基本信息

批准号：
10661491
负责人：
Ambika Goel Bajpayee
金额：
$ 19.12万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2022-07-07 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661491
关键词：
Actomyosin Address Aftercare Animal Model Avidin Back Pain Binding Biochemistry Biological Biomechanics Bolus Infusion Cells Cellular Morphology Charge Chemistry Dextrans Diffusion Disease Dose Drug Delivery Systems Drug Targeting Economic Burden Electrostatics Engineering Extracellular Matrix Extracellular Matrix Degradation Funding Mechanisms Future GTP Phosphohydrolase Activators Glycosaminoglycans Goals Guanosine Triphosphate Phosphohydrolases Height Histology Hydration status In Vitro Inflammatory Injections Injury Intervertebral disc structure Label Low Back Pain Mass Spectrum Analysis Matrix Metalloproteinases Measures Mediating Mediator Modeling Molecular Weight Movement NMR Spectroscopy Nanostructures Nature Needles Operative Surgical Procedures Opiate Addiction Organ Culture Techniques Pain Pain management Patient-Focused Outcomes Penetration Pharmaceutical Preparations Physical therapy Placebos Pre-Clinical Model Property Proteins Puncture procedure Rattus Regulation Saline Signal Transduction Site Structural defect Structure Swelling Symptoms System TNF gene Technology Therapeutic Time Tissues Treatment Efficacy Vertebral column aggrecan clinically relevant conventional therapy cytokine density design disability discogenic pain efficacy testing high reward high risk improved improved outcome in vitro Model in vivo interest intervertebral disk degeneration nanocarrier new therapeutic target novel therapeutics nucleus pulposus patient subsets preclinical study pressure prevent regenerative therapy repaired residence rho rho GTP-Binding Proteins socioeconomics spinal disk injury systemic toxicity transcription factor treatment group

项目摘要

Discogenic back pain, is a leading cause of disability, and involves degenerative changes of the intervertebral disc (IVD). Since only a small subset of patients responds favorably to conventional treatments which address the symptoms but not the disease, there is a need for new therapies to treat disc degeneration (DD). The avascular nature and the dense matrix of the IVD makes it challenging for systemically administered drugs to reach their target cells inside the nucleus pulposus (NP). While local intra-discal injection of therapeutic drugs directly into the NP is a clinically relevant delivery approach, it suffers from low persistence and rapid diffusion from the injection site resulting in short lived benefits, off target effects and potentially, systemic toxicity. In the current proposal, we will develop a charge based (Avidin) nanocarrier system to deliver a months long dose of a large molecular weight drug (CN03) intradiscally to the rat IVD in vivo from a single administration, reducing the often-observed low penetration or short-lived benefits of disease modifying drugs in the IVD. CN03 is a RhoA GTPase activator. We recently discovered are mediated by Rho GTPase regulation of actomyosin contractility. Our study demonstrates that RhoA can regulate the master pro-inflammatory transcription factor NF-ĸB, its downstream signaling including degradative effects at the matrix level, making Rho GTPase mediated actomyosin contractility a novel therapeutic target to prevent pro-inflammatory cytokine induced degradation of the IVD ECM. The goal of this MPI proposal is to test the efficacy of CN03 as a novel therapeutic drug in a preclinical model of IVD degeneration and to design a sustained delivery system for controlled local administration of CN03. In Aim 1, we will quantify actomyosin contractility and biological efficacy of CN03 in a rat IVD puncture injury model. In Aim 2, we will synthesize and characterize an intra-NP drug depot for sustained release of CN03 in rat IVD over a period of 1 month. In Aim 3, we will assess the therapeutic efficacy of CN03 conjugated to Avidin-Dextran in an in vivo rat IVD puncture injury model. Successful completion of these high risk/high reward studies will demonstrate that actoymyosin contractility is an appropriate disease modifying drug target for DD, that Avidin cationic nanostructures can deliver a sustained cargo of a large molecular weight protein up to 1 month in the IVD, and that optimized delivery of CN03 conjugated Avidin-Dextran improves disc functional repair in vivo. These therapeutic strategies are highly translational, and future studies will therefore evaluate these strategies in a large animal model of DD and in treating symptomatic back pain.

椎间盘性背痛，是残疾的主要原因，涉及变化的变化椎间盘（IVD）。由于只有一小部分患者对常规的反应很高解决这些症状但没有解决疾病的治疗方法，需要新的疗法处理圆盘变性（DD）。 IVD的血管性质和密集矩阵具有挑战性的挑战，要全身施用的药物到达核内的靶细胞牙髓（NP）。虽然直接进入NP的局部治疗药物的局部治疗药物是临床相关的输送方法，它的持久性较低和迅速扩散注射部位带来了短暂的生命益处，降低目标效应以及潜在的系统性毒性。当前的建议，我们将开发一个基于费用的（Avidin）纳米载体系统，以提供在体内向大鼠ivd的大分子量药物（CN03）的长剂量长剂量一个政府，降低了经常观察到的低渗透率或短暂的益处 IVD中修饰药物的疾病。 CN03是RhoA GTPase激活剂。我们最近发现由Actomyosin收缩力的Rho GTPase调节介导。我们的研究表明 Rhoa可以调节主要的促炎转录因子NF-ĸB，其下游信号传导包括矩阵级别的降解效应，使Rho GTPase介导肌动球蛋白收缩性是预防促炎细胞因子诱导的新型热靶标 IVD ECM的降解。该MPI提案的目的是测试CN03的效率在IVD变性的临床前模型中的新型热药，并设计持续的 CN03的控制地方给药的输送系统。在AIM 1中，我们将量化Actomyosin CN03在大鼠IVD穿刺损伤模型中的收缩性和生物学效率。在AIM 2中，我们将合成并表征了NP内矿床，以持续释放CN03在大鼠IVD上释放 1个月。在AIM 3中，我们将评估CN03的治疗效率体内大鼠IVD穿刺损伤模型中的Avidin-Dextran。成功完成这些高风险/高奖励研究将表明Actoyososin收缩性是一种适当的疾病修改DD的药物靶标，Avidin阳离子纳米结构可以提供持续的货物在IVD中最多1个月的大分子量蛋白质，并优化了CN03的递送共轭抗生物素 - 脱乳作用可改善体内盘功能修复。这些治疗策略高度翻译，因此未来的研究将在大型动物中评估这些策略 DD的模型和治疗症状的背痛。