miRNA-based therapeutics in polycystic kidney disease

描述(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，囊肿变大，导致肾脏增大和肾功能衰竭。大约一半受影响的人发展为终末期肾脏疾病，需要透析或肾移植。尽管最近取得了进展，但目前还没有FDA批准的疗法来延缓囊肿的生长。MicroRNAs(MiRNAs)是一种抑制基因表达的非编码短小RNA。在许多疾病中观察到miRNA的异常表达，纠正miRNA的表达已成为一种新的治疗方法。在PKD中观察到miRNA表达异常，但miRNAs是否参与了PKD的发病尚不清楚。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小鼠模型中表达上调。利用遗传学方法，我们发现miR-17~92miRNA簇的肾脏特异性过表达足以产生管状囊。相反，肾脏特异性Kif3a突变小鼠(PKD的动物模型)肾小管miR-17~92的基因失活可以延缓囊肿生长，改善肾功能，延长生存期。这些研究已经确定miR-17和相关的miRNAs是PKD中新的囊性生长调节因子。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囊性生长提供了强有力的理论基础。在这一应用中，我们建议测试针对miR-17、miR-18和miR-19家族的小分子抗药作为治疗PKD的药物的可行性。如果成功，结果将验证miR-17/18/19作为PKD新的治疗靶点，并为开发miR-17/18/19抑制剂进行临床前试验奠定基础。

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.