miRNA-based therapeutics in polycystic kidney disease

描述（由申请人提供）：多囊肾病（PKD）是一种常见的遗传性疾病，其特征是肾实质中存在大量充满液体的囊肿。随着时间的推移，囊肿的大小会增加，导致肾脏肿大和肾衰竭。大约一半的受影响个体发展为需要透析或肾移植的终末期肾病。尽管最近取得了进展，但目前没有FDA批准的治疗方法可用于延缓囊肿生长。microRNA（miRNAs）是一种抑制基因表达的短的非编码RNA。在许多疾病中观察到异常的miRNA表达，并且纠正miRNA表达已经成为一种新的治疗方法。在PKD中观察到miRNA表达的失调，但miRNA是否有助于PKD的发病机制尚不清楚。在初步研究中，我们已经确定了促进肾囊肿生长的特定miRNAs。我们发现miR-17、miR-18和miR-19 miRNA家族成员在多种PKD小鼠模型中上调。利用遗传学方法，我们发现肾脏特异性过表达miR-17~92 miRNA簇足以产生管状囊肿。相反，肾脏特异性Kif 3a突变小鼠（PKD动物模型）肾小管中miR-17~92的基因失活可延缓囊肿生长，改善肾功能和肾脏存活率。这些研究已经确立了miR-17和相关miRNA作为PKD囊肿生长的新调节因子。这些研究为确定药物抑制miR-17、miR-18和miR-19 miRNA家族是否延缓PKD囊肿生长提供了强有力的理论依据。在本申请中，我们提出测试针对miR-17、miR-18和miR-19家族的小抗药作为PKD治疗剂的可行性。如果成功，结果将验证miR- 17/18/19作为PKD的新治疗靶点，并为开发用于临床前测试的miR-17/18/19抑制剂奠定基础。

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a common genetic disorder that is characterized by the presence of numerous fluid-filled cysts in the renal parenchyma. The cysts grow in size over time producing kidney enlargement and renal failure. Approximately half of the affected individuals develop end-stage renal disease requiring dialysis or kidney transplantation. Despite recent progress, no FDA-approved therapy is currently available to retard cyst growth. microRNAs (miRNAs) are short non-coding RNAs that inhibit gene expression. Aberrant miRNA expression is observed in numerous diseases and correcting miRNA expression has emerged as a novel therapeutic approach. Dysregulation of miRNA expression is observed in PKD, but whether miRNAs contribute to the pathogenesis of PKD is not known. In preliminary studies, we have identified specific miRNAs that promote kidney cyst growth. We found that members of the miR-17, miR-18 and miR-19 miRNA families are up-regulated in multiple mouse models of PKD. Using genetic approaches, we found that kidney-specific overexpression of the miR-17~92 miRNA cluster is sufficient to produce tubular cysts. Conversely, genetic inactivation of miR-17~92 from renal tubules of kidney-specific Kif3a mutant mice, an animal model of PKD, retards cyst growth, improves renal function and prolongs survival. These studies have established miR-17 and related miRNAs as new regulators of cyst growth in PKD. The studies provide a strong rationale to determine whether pharmaceutical inhibition of miR-17, miR-18 and miR-19 miRNA families retards cyst growth in PKD. In this application, we propose to test the feasibility of small antimirs against the miR-17, miR-18 and miR-19 families as therapeutic agents in PKD. If successful, the results will validate miR- 17/18/19 as new therapeutic targets in PKD, and set the stage to develop miR-17/18/19 inhibitors for pre- clinical testing.