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

摘要 需要治疗肾小球疾病的新方法，因为它们代表着 终末期肾病的第三大常见原因。系统性红斑狼疮致肾脏疾病 (SLEN)是一种肾小球疾病，高达60%的患者肾功能显著下降， 导致终末期肾病的比例约为20%。尽管人们正在探索治疗狼疮的新方法，但他们 一般不会使大多数患者受益，并导致全身免疫抑制，留下大多数人 治疗选择效果较差的人群。此外，新的或旧的治疗方法都没有 评估其针对肾脏的能力，并实现足够的暴露以影响本地化的 疾病过程。发展新的有效的肾脏靶向治疗方法 肾小球疾病，包括肾小球疾病，需要满足临床疗效和安全性需求 患有这些疾病的患者。我们最近发表了关于促进肾脏沉积的研究。 伊马替尼在Slen小鼠模型中的应用，当配方为优化肾脏的纳米乳剂时 曝光。我们的研究结果显示，在MRL/MPJ-Faslpr中，伊马替尼的肾脏沉积增加了三倍 接受我们新的纳米配方的小鼠与免费药物的对比。我们现在将在之后测试新的伊马替尼配方 慢性给药以评估两种slen小鼠模型的疗效和安全性。我们还将对此进行修改 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的制剂， 在Slen的肾小球系膜细胞中表达上调。我们将测试这些提法是否 应用于现有纳米乳剂的技术将促进伊马替尼肾小球沉积和 保留，提高对肾小球系膜细胞的选择性，改善治疗效果，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)前景看好的SLEN疗法可以被配方出来，以增强对疾病肾脏的输送，并有针对性 结构，以及2)代表人类Slen的动物模型将显示出良好的治疗反应， 与免费药物相比，伊马替尼纳米制剂的药代动力学和增强的安全性。研究团队 由在肾小球疾病、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 医疗中心，将协同他们的努力，成功地开发新的战略，以加强肾脏的输送 治疗肾小球疾病的药物积累。

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.