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

项目摘要：常染色体显性遗传性多囊肾病(ADPKD)是最常见的 人类常染色体显性遗传病(5)。在美国大约有60万人，超过10 全世界有数百万人受到影响，造成巨大的医疗负担和病人发病率(6)(7)。ADPKD 其特征是多发性肾囊肿进行性增大，导致肾功能下降。 最终导致50%的患者发生肾功能衰竭(8例)。85%的病例是由PKD1基因突变引起的(9)。在……里面 许多遗传性疾病，如囊性纤维化、疾病发病率和死亡率，都是通过治疗 症状(10)。在ADPKD中，没有减少肾移植需求的治疗方案 (11)。尽管托伐普坦是一种被批准用于ADPKD的药物，但它有明显的副作用和低效率 (12)。显然，仍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 证明囊性纤维化跨膜电导调节器(CFTR)校正剂VX-809可以 减少侵袭性和慢性期小鼠模型的囊性生长和改善肾功能。我们建议 VX-809可用于ADPKD治疗的新假说。这种药已经进入临床了。 使用(13)，可快速用于ADPKD的治疗。其目标是提供强大的机械性 Cftr调制器，如VX-809、VX-661、VX-770将它们向前推进作为治疗的背景 ADPKD，并建立基于重新安排关键输送机制以输送液体的新范式 从包囊里出来。我们提出了三个具体目标：1.增强CFTR的治疗潜力 通过定义调节器如何减小ADPKD的囊泡大小。这一目标将扩大 CFTR调节剂作为ADPKD治疗方法的有效性，并明确表明CFTR校正器可减少 通过促进囊腔内液体的吸收来确定囊腔大小。2.为科学研究提供科学依据 CFTR调节剂在ADPKD治疗中的应用我们假设VX-809在 并将NHE3和ENaC恢复到顶端细胞膜，从而增强 囊液吸收。这一目标将解决这些转运蛋白如何在包囊中异常排列和 如何在治疗上将它们逆转回正常状态。3.推广使用CFTR型调制器来治疗 ADPKD的不同阶段。我们将扩大我们的研究，以评估CFTR校正者单独和在 在早发和晚发小鼠模型中与CFTR增强剂联合使用，模拟不同阶段的 人类疾病。这一目的是为了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，这一点 这项提案意义重大，因为它解决了基于CFTR的ADPKD新疗法的潜力 已被批准临床用于囊性纤维化患者的矫正器。它还建立了一个新的 以促进囊液吸收的药物为基础的治疗模式。

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.