The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation

缺失受体的难题：通过药物受体调节增强功效

• 批准号: 10708018
• 负责人: MARK W. GRINSTAFF
• 金额: $ 65.28万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708018
• 关键词: Acute; Address; Adverse event; Affect; Animals; Articular Range of Motion; Biological Markers; Biological Response Modifier Therapy; CRISPR/Cas technology; Case Study; Cell physiology; Characteristics; Chemosensitization; Chondrocytes; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Collagen; Contracture; Coupled; Cryoelectron Microscopy; Cutaneous; Data; Development; Dexamethasone; Disease; Disease model; Dose; Drug Administration Routes; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug Modulation; Drug Receptors; Drug Targeting; Experimental Designs; Extracellular Matrix Proteins; Fibroblasts; Formulation; G-Protein-Coupled Receptors; Half-Life; Heart failure; Histologic; Hormones; Human; In Vitro; Injections; Intra-Articular Injections; Joints; Kidney; Kinetics; Ligand Binding; Ligands; Lung; Measures; Mechanics; Metalloproteases; Methodology; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Weight; Motivation; Musculoskeletal; Neurology; Oncology; Particle Size; Pathway interactions; Persons; Pharmaceutical Preparations; Polymers; Pregnant Women; Property; Proteins; Receptor Up-Regulation; Recovery; Regulation; Relaxin; Reporting; Role; Safety; Saline; Serum; Shoulder; Signal Pathway; Signal Transduction; Small Interfering RNA; Specificity; Structure; Symptoms; Synovial Fluid; System; Systemic Scleroderma; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; United States; Validation; antifibrotic treatment; biocompatible polymer; biodegradable polymer; canine model; cartilaginous; clinical efficacy; clinical translation; clinically relevant; coronary fibrosis; cost; crystallinity; cytotoxicity; density; design; disease phenotype; experimental study; frontier; improved; improved outcome; in vivo; insight; joint stiffness; knock-down; member; novel; particle; peptide hormone; preclinical efficacy; prevent; programs; rational design; receptor; receptor binding; receptor density; receptor expression; receptor upregulation; skin fibrosis; small molecule; stem; targeted delivery; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT This proposal outlines an advanced drug delivery methodology, argues for the power of biotherapeutics, and demonstrates increased biotherapeutic efficacy through receptor upregulation. The benefit of specificity that is inherent to targeted biotherapeutics comes at the cost of predicated efficacy based on the cognate receptor being present at a high enough density to achieve a therapeutic effect. Current advances in delivery systems are enabling localized and prolonged drug release. However, localization is only one component of effective drug administration. Here, we propose an advanced drug delivery system, rationally designed to potentiate drug activity while simultaneously localizing and prolonging biotherapeutic concentration. As a clinically relevant example, this proposal outlines the coordinated localization and potentiation of the natural antifibrotic peptide hormone, relaxin-2 (RLX), and its receptor, RXFP1, to both treat the underlying causes of shoulder contracture and to restore joint range of motion. RLX remodels extracellular matrix (ECM) proteins via upregulating matrix metalloproteases (MMPs) and decreasing collagen levels. We recently made the exciting discovery that dexamethasone (DEX) increases RXFP1 expression in fibrotic synoviocytes and further exploration of the molecular mechanism of actions of RLX and DEX will enhance rational drug design. We will test the hypothesis that co-administration of RLX and DEX from polymeric microparticles (MPs) via a local single intraarticular (IA) injection into the synovial space, will rapidly alleviate arthrofibrosis symptoms (increased joint stiffness and decreased range of motion, ROM) and reduce fibrotic tissue accumulation in the afflicted joint. Further, DEX potentiation of RLX’s antifibrotic activity will decrease the minimum effective dose and increase recovery rate by modulating RXFP1 receptor density. Successful completion of this proposal will provide a novel treatment for arthrofibrosis, a debilitating condition which affects more than 15 million people in the United States, and demonstrate the importance of both delivering a biotherapeutic while also increasing the target receptor density to maximize efficacy. Importantly, significant preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address these hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 determines RLX’s ligand-receptor binding mechanics and the novel role of TGF-β1 and DEX in regulating RXFP1 expression, as well as RLX’s antifibrotic mechanism of action. Aim 2 identifies the material property characteristics of biodegradable and biocompatible polymeric MPs loaded with either DEX or RLX. Aim 3 evaluates the pharmacokinetics and efficacy of the optimal DEX MP + RLX MP codelivery formulation cocktail identified in Aim 2 using an established in vivo shoulder contracture model.

项目摘要/摘要 该提议概述了一种先进的药物输送方法，主张生物治疗学的力量，以及 证明通过受体上调提高了生物治疗效率。特异性的好处是 针对性的生物治疗剂固有的是基于同源接收器的预测效率的代价 以足够高的密度存在以达到治疗作用。当前的交付系统进展 正在实现局部和延长药物释放。但是，本地化只是有效药物的一部分 行政。在这里，我们提出了一个先进的药物输送系统，理性旨在增强药物 活性同时定位并延长生物治疗浓度。作为临床相关的 例如，该提案概述了天然抗纤维化胡椒的协调定位和潜力 HorseOne，halex-2（RLX）及其接收器RXFP1，都可以治疗肩膀签约的根本原因 并恢复关节运动范围。 RLX通过上调基质重塑细胞外基质（ECM）蛋白 金属蛋白酶（MMP）并降低胶原蛋白水平。我们最近做出了令人兴奋的发现 地塞米松（DEX）增加了纤维化滑膜细胞中RXFP1的表达，并进一步探索了 RLX和DEX作用的分子机制将增强合理的药物设计。我们将检验假设 通过局部单个关节内（IA），来自聚合微粒（MP）的RLX和DEX共同给药 注入滑膜空间，将迅速减轻关节纤维化症状（增加关节刚度和 运动范围降低，ROM）并减少了受苦的关节中的纤维化组织积累。此外，dex RLX抗纤维化活性的增强将降低最低有效剂量，并提高恢复率 调节RXFP1受体密度。该提案的成功完成将为 关节纤维化，一种令人衰弱的状况，影响了美国超过1500万人，并且 证明既输送生物疗法的同时又增加了靶受体密度的重要性 重要的是，大量的初步数据支持拟议的研究，良好的研究 建立了材料和严格的实验设计，以及基本的跨学科合作和 有专业知识可以解决这些假设。该五年提案的具体目的如下。 AIM 1确定RLX的配体 - 受体结合力学以及TGF-β1和DEX在调节中的新作用 RXFP1表达以及RLX的抗纤维化作用机理。 AIM 2标识物质属性 可生物降解和生物相容性的聚合物MP的特征，带有DEX或RLX。目标3 评估最佳DEX MP + RLX MP Codelivery公式鸡尾酒的药代动力学和效率 使用已建立的体内肩部缔合模型在AIM 2中识别。