PKD1 derepression as a potential therapy for Polycystic Kidney Disease

摘要 常染色体显性遗传性多囊肾病（ADPKD）是最常见的单基因遗传病之一， 疾病，估计全球患病率为1250万人。不幸的是，>50% ADPKD患者发展为终末期肾衰竭，治疗选择仍然有限。最近 研究指出PKD 1基因剂量减少是许多ADPKD患者的疾病机制。 这一发现打开了一扇令人兴奋的可能性之门，即逆转PKD 1的下降可能会阻止 ADPKD在这些人。然而，尽管有变革的潜力，没有PKD 1靶向药物， 正在接受临床研究我们在这个应用程序中的目标是提供一个科学的路线图， 开发一种新的PKD 1增强治疗方法。我们提出了一个新颖的想法，沿着 种系突变，非失活PKD 1等位基因产生的mRNA翻译效率低下 也有助于降低PKD 1剂量并减少ADPKD。这个想法源于我们的 初步研究，我们发现从PKD 1 3 '- UTR足以改善mRNA翻译并提高PC 1水平。反过来，这种方法 改善小鼠和体外人ADPKD模型中的囊肿生长。基于这些有希望的 观察，我们建议：（1）使用遗传原理证明方法来研究 在ADPKD小鼠和人模型中PKD 1去阻遏，和（2）测试 竞争性胜过并阻止miR-17与PKD 1结合的寡核苷酸， 提高PC 1水平。

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is amongst the most common monogenetic disorders, with an estimated prevalence of 12.5 million people worldwide. Unfortunately, >50% of ADPKD patients develop end-stage renal failure and treatment options are still limited. Recent studies point to reduced PKD1 gene dosage as the disease mechanism for many ADPKD patients. This revelation opens the door to an exciting possibility that reversing PKD1 decline may arrest ADPKD in these individuals. However, despite the transformative potential, no PKD1-targeting drugs are under clinical investigation. Our goal in this application is to provide a scientific roadmap for developing a novel PKD1-boosting therapeutic approach. We propose a novel idea that along with the germline mutation, inefficient translation of mRNAs produced by the non-inactivated PKD1 allele also contributes to the lower PKD1 dosage and aggravates ADPKD. This idea emanates from our preliminary studies, where we found that deleting the cis-inhibitory miR-17 motif from the PKD1 3’- UTR is sufficient to improve mRNA translation and to raise PC1 levels. In turn, this approach ameliorates cyst growth in mice and in vitro human ADPKD models. Based on these promising observations, we propose: (1) using genetic proof-of-principle approaches to study the impact of PKD1 derepression in ADPKD mouse and human models, and (2) test the feasibility of oligonucleotides that outcompete and prevent miR-17 from binding to PKD1 as novel therapeutics to raise PC1 levels.