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

• 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
• 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

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.

椎间盘源性背痛是残疾的主要原因，涉及椎间盘的退行性变化。 椎间盘（IVD）。由于只有一小部分患者对常规化疗反应良好， 虽然治疗方法可以解决症状但不能解决疾病，但需要新的治疗方法， 治疗椎间盘退变（DD）。IVD的无血管性质和致密基质使其 全身给药的药物难以到达细胞核内的靶细胞 髓（NP）。虽然直接将治疗药物局部椎间盘内注射到NP中是一种有效的方法， 在临床相关的递送方法中，它具有低持久性和从微生物学中的快速扩散。 注射部位，导致短期受益、脱靶效应和潜在的全身毒性。在 根据目前的建议，我们将开发一种基于电荷的（抗生物素蛋白）纳米载体系统， 在大鼠体内椎间盘内注射大分子量药物（CN 03）， 单次给药，减少了经常观察到的低渗透性或短期获益， IVD中的疾病修饰药物。CN 03是RhoA GT3激活剂。我们最近发现 由Rho GT3调节肌动球蛋白收缩性介导。我们的研究表明， RhoA可以调节主促炎转录因子NF-κ B及其下游转录因子NF-κ B， 信号传导，包括基质水平的降解作用，使Rho GT3介导 肌动球蛋白收缩性是预防促炎细胞因子诱导的新的治疗靶点 IVD ECM的降解。本MPI提案的目标是测试CN 03作为 在IVD变性的临床前模型中的新型治疗药物，并设计持续的 用于CN 03的受控局部施用的递送系统。在目标1中，我们将定量肌动球蛋白 在大鼠IVD穿刺损伤模型中CN 03的收缩性和生物学功效。在目标2中，我们将 合成并表征用于在大鼠IVD中持续释放CN 03 NP内药物贮库， 为期一个月。在目标3中，我们将评估与C12 H12 O2缀合的CN 03的治疗功效。 在体内大鼠IVD穿刺损伤模型中的抗生物素蛋白-葡聚糖。圆满完成这些高 风险/高回报研究将证明， 修饰DD的药物靶点，亲和素阳离子纳米结构可以递送持续的 在IVD中长达1个月的大分子量蛋白，并且优化了CN 03的递送 缀合的抗生物素蛋白-葡聚糖改善体内椎间盘功能修复。这些治疗策略 是高度翻译的，因此未来的研究将在大型动物中评估这些策略 DD模型和治疗症状性背痛。