Therapeutic Use of mTOT Modulators in Polycystic Kidney Disease

 描述（由申请人提供）：多囊肾病（PKD）是一个术语，适用于一组遗传性疾病，其特征是肾脏中存在囊肿，尽管多个器官通常受到影响。在基本上所有形式的PKD中发现的肾脏病理包括液体分泌增加、基质重塑、细胞增殖和凋亡，以及肾囊肿衬里上皮细胞的分化改变。PKD代表以常染色体显性（AD）或常染色体隐性性状遗传的病症。ADPKD发生在1/500到1/1000的个体中，主要是由于PKD 1或PKD 2两个基因之一的突变。这些突变驱动导致AMPK失活和mTOR和Wnt信号传导途径过度活化的病理，导致肾单位小管内衬上皮细胞的不适当细胞增殖。目前，还没有批准用于阻止PKD进展的治疗干预。代谢解决方案开发公司（MSDC; www.msdrx.com）正在开发新型胰岛素增敏剂，其与新鉴定的线粒体靶点（mTOT，噻唑烷二酮的线粒体靶点）相互作用，同时避免激活PPAR？受体。这些药物已在II期临床试验中显示出对2型糖尿病的疗效，并在组织特异性/代谢需求的基础上调节从丙酮酸到线粒体基质的碳流。这些化合物对mTOT的调节引起信号传导途径的变化，包括在糖尿病开发计划中使用的细胞和动物模型中激活AMPK和抑制mTOR和Wnt信号传导途径。由于信号通路的这些变化与PKD中观察到的变化方向相反，MSDC评价了这些mTOT调节胰岛素增敏剂在动物PKD模型中的潜在治疗用途，发现它们减少了肾脏和肝脏囊肿体积。此外，在对mTOT调节剂影响ADPKD患者来源的人囊性上皮细胞中信号传导途径的能力的初步评估中，观察到AMPK的活化。因此，本次I期SBIR资助申请的总体目标是确定哪种mTOT调节剂有可能在人类ADPKD治疗中最有效。将选择具有限制ADPKD患者来源的囊性上皮细胞生长的最佳特征的药物进行进一步的临床前开发。这项未来的工作将是第二阶段SBIR赠款申请的主题。本研究工作的总体目标是开发一种mTOT调节胰岛素增敏剂，用于PKD患者临床试验中的治疗干预。

 DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a term applied to a group of inherited disorders characterized by the presence of cysts in the kidney although multiple organs are typically affected. Renal pathologies found in essentially all forms of PKD include increased fluid secretion, matrix remodeling, cellular proliferation, and apoptosis, with a altered differentiation of the epithelial cells lining the renal cysts. PKD represent conditions tht are inherited as either autosomal dominant (AD) or autosomal recessive traits. ADPKD occurs in 1-in-500 to 1-in-1000 individuals, primarily as a result of mutations in one of two genes, PKD1 or PKD2. These mutations drive a pathology which results in inactivation of AMPK and over-activation of mTOR and Wnt signaling pathways leading to inappropriate cellular proliferation of the epithelial cells lining the tubules of the nephron. At this time, there is no therapeutic intervention approved for halting PKD progression. Metabolic Solutions Development Company (MSDC; www.msdrx.com) is developing novel insulin sensitizing agents which interact with a newly identified mitochondrial target (mTOT, mitochondrial Target of the Thiazolidinediones) while sparing activation of the PPAR¿ receptor. These agents have shown efficacy in Phase II clinical trials for type 2 diabetes and modulate carbon flow from pyruvate into the mitochondrial matrix on a tissue specific/metabolic demand basis. Modulation of mTOT by these compounds elicits changes in signaling pathways that include activation of AMPK and inhibition of mTOR and the Wnt signaling pathways in cell and animal models used in the diabetes development program. Since these changes in signaling pathways are in the opposite direction of that seen in PKD, MSDC evaluated the potential therapeutic use of these mTOT modulating insulin sensitizing agents in an animal PKD model and found that they reduced kidney and liver cyst volume. Furthermore, in an initial assessment of the ability of mTOT modulating agents to influence signaling pathways in human cystic epithelial cells derived from ADPKD patients, activation of AMPK was observed. Thus, the overall objective of this Phase I SBIR grant application is to determine which mTOT modulating agent has the potential to be the most effective in human ADPKD therapy. The agent with the best profile for limiting growth of cystic epithelial cells derived from ADPKD patients will be selected for further preclinical development. This future work will be the subject of a Phase II SBIR grant application. The overarching goal of this research effort is to develop a mTOT modulating insulin sensitizing agent for therapeutic intervention in a clinical trial of PKD patients.