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 这项提案概述了一种先进的药物输送方法，论证了生物疗法的力量，以及 通过上调受体来提高生物治疗效果。专一性的好处就是 靶向生物疗法固有的代价是基于同源受体的预测疗效。 以足够高的密度存在以达到治疗效果的。递送系统的最新进展 使得局部和长期的药物释放成为可能。然而，本地化只是有效药物的一个组成部分。 行政管理。在这里，我们提出了一种先进的药物输送系统，合理设计以增强药物 活性，同时定位和延长生物治疗浓度。作为一种临床上相关的 例如，该提案概述了天然抗纤维化多肽的协调定位和增强作用 激素松弛素-2(RLX)及其受体RXFP1均可治疗肩挛缩症的潜在原因 并恢复关节活动范围。RLX上调基质重塑细胞外基质(ECM)蛋白 金属蛋白酶(MMPs)和降低胶原蛋白水平。我们最近有了一个令人兴奋的发现 地塞米松增加纤维化滑膜细胞中RXFP1的表达及其机制的进一步探讨 RLX和DEX作用的分子机制将促进合理的药物设计。我们将检验这一假设 局部单次关节内注射RLX和DEX的实验研究 向滑膜间隙注射，将迅速缓解关节纤维化症状(关节僵硬和 减少活动范围)，并减少纤维组织在受影响的关节积聚。此外，DEX 增强RLX的抗纤维化活性将降低最小有效剂量并提高治愈率 调节RXFP1受体密度。这项提议的成功完成将提供一种新的治疗方法 关节纤维化，这是一种使人虚弱的疾病，在美国影响着1500多万人，以及 证明既要提供生物治疗，又要增加靶受体密度的重要性 最大限度地发挥功效。重要的是，重要的初步数据支持拟议的研究，特征良好 建立了材料和严格的实验设计，以及基本的跨学科合作和 解决这些假设的专业知识已经到位。这一五年计划的具体目标如下。 目的1确定RLX的配体-受体结合机制以及转化生长因子-β1和地塞米松在调节中的新作用 RXFP1的表达，以及RLX的抗纤维化作用机制。目标2确定材料属性 负载DEX或RLX的可生物降解和生物相容的聚合物MPS的特性。目标3 评价最佳地塞米松MP+RLX MP联合制剂鸡尾酒的药代动力学和疗效 使用已建立的活体肩部痉挛模型，在目标2中确定。