Developing a New Therapeutic Approach for Autosomal Dominant Polycystic Kidney Disease.

常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性肾病。 人类常染色体显性遗传病（5）。美国约有60万人， 全世界有100万人受到影响，造成巨大的医疗负担和患者发病率（6）（7）。ADPKD 肾囊肿的特点是多个肾囊肿的进行性增大，导致肾功能下降 并在50%的患者中最终导致肾衰竭（8）。85%的病例由PKD 1突变引起（9）。在 许多遗传性疾病如囊性纤维化、疾病发病率和死亡率通过治疗 症状（10）在ADPKD中，没有治疗方案可以减少肾移植的需要 （十一）、虽然托伐普坦是批准用于ADPKD的药物，但其副作用明显，效率低 （12）.显然，仍然迫切需要开发新的治疗方法。我们提供了令人信服的初步数据 表明VX-809，一种囊性纤维化跨膜传导调节因子（CFTR）校正剂， 在侵袭性和缓慢发病小鼠模型中减少囊肿生长并改善肾功能。我们提出 VX-809可用于治疗ADPKD的新假设。这种药物已经在临床上 使用（13），可以快速跟踪ADPKD的治疗。目标是提供一个强大的机械 CFTR调节剂如VX-809、VX-661、VX-770的背景，以使它们作为治疗 ADPKD和建立一个新的范式的基础上重新安排关键的运输机制，以运输液体 从囊肿里取出来我们提出三个具体目标：1.增强CFTR的治疗潜力 通过定义它们如何减少ADPKD中的囊肿大小来确定调节剂。目的是扩大 CFTR调节剂作为ADPKD治疗的有用性，并明确显示CFTR校正剂降低了 通过促进囊腔中液体的吸收来控制囊肿的大小。2.提供科学基础， CFTR调节剂治疗ADPKD的治疗用途。我们假设VX-809稳定了CFTR， 基底外侧细胞膜和恢复NHE 3和ENaC顶端细胞膜，从而增强 囊液吸收。本目标将解决这些转运蛋白如何在囊肿中异常排列， 如何在治疗上恢复正常3.将CFTR调节剂的使用扩展到治疗 ADPKD的不同阶段我们将扩大我们的研究，以评估CFTR校正剂单独和联合应用的作用。 在早发性和迟发性小鼠模型中与CFTR增效剂组合，其模拟不同阶段的 人类疾病该目的旨在证明长期治疗的有效性。 意义：到目前为止，还没有治疗ADPKD的方法可以减少肾移植的需要。因此， 该提案非常重要，因为它解决了基于CFTR的ADPKD新疗法的潜力 已经被批准用于囊性纤维化患者的临床使用的矫正剂。它还建立了一个新的 基于促进囊液吸收的药物的治疗范例。

Project Summary: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common autosomal dominant disorder in humans (5). Approximately 600,000 people in the U.S. and more than 10 million people world-wide are affected, causing a large heath care burden and patient morbidity (6)(7). ADPKD is characterized by a progressive enlargement of multiple renal cysts that leads to a decline in renal function and culminates in renal failure in 50% of all patients (8). 85% of the cases caused by mutations in PKD1 (9). In many genetic disorders such as cystic fibrosis, disease morbidity and mortality are delayed by treatment of the symptoms (10). In ADPKD, there is no treatment regimen that reduces the need for renal transplants (11). Although tolvaptan is a drug approved for ADPKD, it has significant side effects and low efficiency (12). Clearly, there is still a critical need to develop new treatments. We provide compelling preliminary data demonstrating that VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) corrector, can reduce cyst growth and improve renal function in both aggressive and slow-onset mouse models. We propose the novel hypothesis that VX-809 can be used as a treatment for ADPKD. This drug is already in clinical use (13) and can be fast-tracked for the treatment of ADPKD. The goal is to provide a strong mechanistic background for CFTR modulators such as VX-809, VX-661, VX-770 to move them forward as a treatment for ADPKD and to establish a new paradigm based on rearranging key transport mechanisms to transport fluid out of the cysts. We are proposing three Specific Aims to: 1. Enhance the therapeutic potential of CFTR modulators by defining how they reduce cyst size in ADPKD. The aim will expand the scope of the usefulness of CFTR modulators as a therapy for ADPKD and show definitively that CFTR correctors reduce cyst size by promoting the absorption of fluid from the cyst lumen. 2. Provide a scientific foundation for the therapeutic use of CFTR modulators to treat ADPKD. We hypothesize that VX-809 stabilizes CFTR in the basolateral cell membrane and restores NHE3 and ENaC to the apical cell membrane, thereby enhancing the absorption of cyst fluid. This Aim will address how these transporters are abnormally arranged in cysts and how they can be reversed back to normal, therapeutically. 3. Extend the use of CFTR modulators to treat different stages of ADPKD. We will expand our study to evaluate the action of CFTR correctors alone and in combination with CFTR potentiators in early- and late-onset mouse models, which mimic different stages of human disease. This Aim is designed to demonstrate the efficiency of long-term treatment. Significance: As of yet, there is no therapy for ADPKD that reduces the need for a renal transplant. Thus, this proposal is highly significant because it addresses the potential for a new therapy for ADPKD based upon CFTR correctors that are already approved for clinical use for patients with cystic fibrosis. It also establishes a new therapeutic paradigm based upon drugs that promote fluid absorption out of the cysts.