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 i s 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.

Public Health Relevance

Adult autosomal dominant polycystic kidney disease is a genetic disease which causes a progressive enlargement of multiple renal cysts, leading to renal failure in 50% of patients. The goal is to develop a therapy based on reducing cyst growth.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Maric-Bilkan, Christine
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Johns Hopkins University
Internal Medicine/Medicine
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United States
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