Therapeutic Use of mTOT Modulators in Polycystic Kidney Disease

 描述(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性病变，尽管通常会影响到多个器官。基本上在所有形式的PKD中都可发现肾脏病理改变，包括液体分泌增加、基质重塑、细胞增殖和细胞凋亡，并伴有肾囊内上皮细胞分化的改变。PKD代表常染色体显性遗传(AD)或常染色体隐性遗传的条件。ADPKD发生在每500人中有1人到1000人中有1人，主要是由于PKD1或PKD2两个基因中的一个发生突变。这些突变导致AMPK失活，mTOR和Wnt信号通路过度激活，导致肾小管上皮细胞不适当的细胞增殖。目前，还没有批准的治疗干预措施来阻止PKD的进展。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，这种增敏剂可以与新发现的线粒体靶点(MTOT，噻唑烷二酮的线粒体靶标)相互作用，同时避免激活PPAR？受体。这些药物已经在治疗2型糖尿病的第二阶段临床试验中显示出有效性，并根据组织特定/代谢需求调节从丙酮酸到线粒体基质的碳流。这些化合物对MTOT的调节引起了信号通路的变化，包括激活AMPK，抑制用于糖尿病发展计划的细胞和动物模型中的mTOR和Wnt信号通路。由于这些信号通路的变化与PKD的变化方向相反，MSDC在动物PKD模型中评估了这些MTOT调节的胰岛素增敏剂的潜在治疗用途，发现它们减少了肾和肝脏的囊性体积。此外，在初步评估MTOT调节剂影响ADPKD患者来源的人囊上皮细胞信号通路的能力时，观察到AMPK的激活。因此，第一阶段SBIR赠款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。ADPKD患者来源的囊性上皮细胞生长受到最佳限制的药物将被选择用于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。这项研究的主要目标是开发一种MTOT调节的胰岛素增敏剂，用于PKD患者的临床试验的治疗干预。

 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.