IND 117464 Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease

目前迫切需要一种安全、廉价的治疗方法，可以延缓囊肿扩大的进展 以及伴随的肾实质破坏，在大多数人中导致肾衰竭。 常染色体多囊肾病（ADPKD）患者。在ADPKD中，治疗开始越早， 对患者的潜在获益更大，因此，应考虑终身使用这种疾病的药物 疗法我们的总体目标是开发有效的药物，从诊断开始就可以安全使用 在ADPKD患者中。拟议研究的目的是对药物进行初步评价。 使用低剂量胰岛素增敏剂、PPARγ激动剂吡格列酮治疗 ADPKD。我们之前的细胞培养研究表明，低剂量的PPARγ激动剂（包括吡格列酮）， 抑制CFTR（囊性纤维化跨膜传导调节因子）Cl-通道的合成， 肾囊肿的症状有哪些？CFTR是主要的离子通道，被假定参与跨上皮细胞介导的细胞内信号传导。 Cl-，其次，水流入囊肿腔，导致囊肿扩张。我们的体内动物研究 已经证明两种FDA批准的PPARγ激动剂，吡格列酮或罗格列酮， 在PKD的PCK大鼠模型中。除了抑制囊肿生长外，预期PPARγ激动剂疗法 对PKD的其他参数，如血脂异常、高血压和内皮 功能基于这些数据，我们假设低剂量吡格列酮治疗会减缓 囊肿扩张在人类ADPKD患者和延缓疾病的进展。拟定研究 是一项吡格列酮（15 mg/天）与安慰剂治疗的双盲、安慰剂对照、交叉试验， ADPKD的治疗该研究是一项先导性研究，旨在测试吡格列酮减缓 通过MRI测量的肾脏体积变化百分比评估PKD进展，与 安慰剂将入组28例受试者。一年的交叉设计提供了最好的机会， 通过允许每例患者作为其自己的患者，在短期方案中获得有意义的安全性和疗效数据 控制这将有助于未来多中心随机试验的设计。根据大数据 在正常志愿者和糖尿病患者中进行的规模研究表明，低剂量吡格列酮长期相对安全 长期治疗。因此，这种药物可能为ADPKD患者的治疗提供一种安全的选择， 在生命的长度和质量上。

There is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that leads to renal failure in the majority of autosomal polycystic kidney disease (ADPKD) patients. In ADPKD, the earlier the onset of treatment, the greater the potential benefit to the patient, therefore, drugs for this disease should be considered life-long therapy. Our overall goal is to develop efficacious drugs that can be safely used from the time of diagnosis in ADPKD patients. The objective in the proposed studies is to conduct a preliminary evaluation of drug therapy using a low dose of an insulin sensitizing agent, the PPARγ agonist, pioglitazone, in the treatment of ADPKD. Our previous cell culture studies showed that low doses of PPARγ agonists, including pioglitazone, inhibit the synthesis of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl- channel in the cell type that lines the renal cysts. CFTR is the major ion channel postulated to be involved in transepithelial Cl- and, secondarily, water flux into the cyst lumen resulting in cyst expansion. Our in vivo animal studies have shown that the two FDA approved PPARγ agonists, pioglitazone or rosiglitazone, inhibited cyst growth in the PCK rat model of PKD. In addition to inhibiting cyst growth, PPARγ agonist therapy is expected to have beneficial effects on other parameters of PKD such as dyslipidemia, hypertension and endothelial function. Based on these data, we hypothesize that treatment with low dose pioglitazone will slow cyst expansion in human ADPKD patients and delay the progression of disease. The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone (15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI compared to one year of placebo. 28 subjects will be enrolled. A one year cross-over design provides the best opportunity to obtain meaningful safety and efficacy data in a short term protocol by allowing each patient to serve as his/her own control. This will facilitate the design of a future multi center randomized trial. Based on data from large scale studies in normal volunteers and diabetic patients, low dose pioglitazone is relatively safe for long term treatment. Thus, this drug may provide a safe option for treatment of ADPKD patients and an increase in length and quality of life.