Diversification of Glomerular Kidney Disease Treatments By Targeting Therapeutics to the Kidney

通过针对肾脏的治疗来实现肾小球肾病治疗的多样化

基本信息

批准号：
10808617
负责人：
MELANIE S JOY
金额：
$ 36.79万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2025-09-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10808617
关键词：
Acute Animal Model Annexins Biodistribution Characteristics Charge Chronic Colorado Deposition Development Dialysis procedure Disease Dose Drug Delivery Systems Drug Formulations Drug Kinetics End stage renal failure Exhibits Exposure to Formulation Glomerular Mesangial Cell Grant Growth Factor Receptors Human Imatinib Immunoglobulin Fragments Immunosuppression In Vitro Kidney Kidney Diseases Ligands Link Localized Disease Lupus Lupus Nephritis Medical center Morbidity - disease rate Mus Oils PDGFRB gene Particle Size Pathology Patients Pharmaceutical Preparations Pharmacodynamics Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Population Process Proteins Publishing Renal function Renal glomerular disease Research Risk Safety Schools Scientist Structure Survival Rate Systemic Lupus Erythematosus Techniques Testing Therapeutic Toxic effect Toxicology Translating Treatment Efficacy Universities Water clinical efficacy drug development effective therapy efficacy evaluation improved in vivo mesangial cell mortality mortality risk mouse model nanoemulsion nanoformulation novel novel strategies pre-clinical receptor side effect synergism systemic toxicity targeted treatment treatment response uptake

项目摘要

ABSTRACT Novel approaches to the treatment of glomerular kidney diseases are needed given that they represent the third most common cause of end stage renal disease. Systemic lupus erythematosus induced kidney disease (SLEN) is one glomerular disease where up to 60% of patients exhibit significant declines in kidney function, resulting in end stage renal disease in ~20%. Although novel treatments are being explored for lupus, they generally do not benefit the majority of patients and cause systemic immunosuppression, leaving the majority of the population with less effective treatment options. Additionally, neither new nor old treatments have been evaluated for their ability to target to the kidney and achieve sufficient exposure to influence the localized disease processes. The development of novel and effective renal targeted treatment approaches for glomerular kidney diseases, including SLEN, are needed to meet the clinical efficacy and safety needs of patients with these disorders. We have recently published research for enhanced kidney deposition of imatinib in a murine model of SLEN, when formulated in a nanoemulsion developed to optimize kidney exposure. Results from our studies showed three-fold higher kidney deposition of imatinib in MRL/MpJ-Faslpr mice that received our novel nanoformulation vs. free drug. We will now test the novel imatinib formulation after chronic dosing to evaluate efficacy and safety in two mouse models of SLEN. We will also modify this formulation by linking a relevant ligand or an antibody fragment to target a receptor and protein, respectively, that are upregulated in glomerular mesangial cells in SLEN. We will test whether these formulation techniques applied to the existing nanoemulsion will enhance imatinib glomerular deposition and retention, improve selectivity for targeting mesangial cells, improve therapeutic efficacy and provide relative safety, as compared to our primary formulation. The central hypotheses of our research are that 1) promising SLEN treatments can be formulated to enhance delivery to the diseased kidney and targeted structures, and 2) animal models that represent human SLEN will demonstrate favorable treatment responses, pharmacokinetics, and enhanced safety with imatinib nanoformulations vs. free drug. The research team comprised of scientists with diverse backgrounds in glomerular kidney diseases, drug development, nanoformulations, toxicology, and renal pathology across schools at the University of Colorado Anschutz Medical Center, will synergize their efforts to successfully develop novel strategies to enhance kidney delivery and accumulation of therapeutics for the treatment of glomerular kidney diseases.

抽象的鉴于它们代表了肾小球肾脏疾病的新颖方法终阶段肾脏疾病的第三最常见原因。全身性红斑狼疮诱导肾脏疾病（Slen）是一种肾小球疾病，其中多达60％的患者在肾功能下显示出明显下降，导致末期肾脏疾病约为20％。尽管正在为狼疮探索新颖的治疗方法通常不会使大多数患者受益，并引起全身免疫抑制，使大多数人口的治疗选择较低。此外，新疗法既不是评估其靶向肾脏并实现足够暴露以影响本地化的能力疾病过程。开发新颖有效的肾脏靶向治疗方法需要肾小球肾脏疾病，包括SLEN，以满足临床功效和安全需求患有这些疾病的患者。我们最近发表了研究以增强肾脏沉积的研究伊马替尼（Imatinib 接触。我们的研究结果表明，伊马替尼在MRL/MPJ-FASLPR中的三个高肾脏沉积接受我们新颖的纳米制剂与免费药物的小鼠。现在，我们将测试新颖的伊马替尼配方慢性剂量以评估两种小鼠SLEN模型的功效和安全性。我们还将修改此通过将相关配体或抗体片段分别靶向受体和蛋白质的抗体片段来制定。在Slen的肾小球肾小球细胞中上调。我们将测试这些配方是否应用于现有纳米乳液的技术将增强伊马替尼的肾小球沉积和保留，提高靶向肾小球细胞的选择性，提高治疗功效并提供相对安全，与我们的主要配方相比。我们研究的中心假设是 1）可以制定有希望的Slen治疗以增强患病肾脏的递送并针对性结构和2）代表人类Slen的动物模型将显示出良好的治疗反应，药代动力学，并通过伊马替尼纳米成型与免费药物增强安全性。研究团队由肾小球肾脏疾病的科学家组成，药物开发，科罗拉多大学Anschutz大学的纳米制剂，毒理学和肾脏病理学医疗中心，将协同他们成功制定新型策略以增强肾脏的努力以及用于治疗肾小球肾脏疾病的治疗剂的积累。