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

• 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
• 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

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.

摘要 考虑到肾小球肾病代表了肾小球疾病，因此需要治疗肾小球肾病的新方法。 第三大最常见的原因是终末期肾病。系统性红斑狼疮肾病 （SLEN）是一种肾小球疾病，其中高达60%的患者表现出肾功能的显著下降， 导致约20%的终末期肾病。虽然新的治疗方法正在探索狼疮， 通常不会使大多数患者受益，并引起全身免疫抑制， 有效治疗方案较少的人群。此外，无论是新的还是旧的治疗方法， 评价其靶向肾脏并实现足够暴露以影响局部 疾病过程。新型有效的肾脏靶向治疗方法的开发 肾小球肾病，包括SLEN，需要满足临床疗效和安全性需求 这些疾病的患者。我们最近发表了一项研究， 伊马替尼在SLEN小鼠模型中的作用，当配制成纳米乳剂时， exposure.我们的研究结果显示，MRL/MpJ-Faslpr中伊马替尼的肾脏沉积高出三倍 接受我们的新型纳米制剂与游离药物的小鼠。我们现在将测试新的伊马替尼制剂， 长期给药以评估在两种SLEN小鼠模型中的功效和安全性。我们还将修改此 通过将相关配体或抗体片段分别连接到靶向受体和蛋白质， 在SLEN的肾小球系膜细胞中上调。我们将测试这些配方是否 应用于现有纳米乳剂的技术将增强伊马替尼肾小球沉积， 保留，提高靶向系膜细胞的选择性，提高治疗功效，并提供 相对安全性，与我们的主要配方相比。我们研究的主要假设是， 1)可以配制有前景的SLEN治疗以增强对患病肾脏的递送， 结构，和2）代表人SLEN的动物模型将显示有利的治疗反应， 与游离药物相比，伊马替尼纳米制剂具有更好的药代动力学和更高的安全性。研究团队 由在肾小球肾病，药物开发， 科罗拉多大学安舒茨分校的纳米制剂、毒理学和肾脏病理学 医学中心，将协同努力，成功地开发新的战略，以提高肾脏交付 和积累用于治疗肾小球肾病的治疗剂。