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

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.

Grant Number: 5R01DK125272-05
NIH Institute/Center: NIH
Principal Investigator: Liudmila Cebotaru