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Abstract: SA-PO781

CFTR Modulators Mitigate Autosomal Recessive Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Ciobanu, Cristian, Johns Hopkins University, Baltimore, Maryland, United States
  • Cebotaru, Liudmila, Johns Hopkins University, Baltimore, Maryland, United States

ARPKD caused by mutations in PKHD1 results in systemic and portal hypertension, fibrosis of the liver, hepatosplenomegaly, and fusiform dilation of the collecting ducts that progresses to end-stage renal disease.


We injected in pkhd1del3-4/del3-4 (del3-4) deletion model mice with 30 mg/kg of VX-809 every other day for 30 days beginning at 5 days of age or 4 months old and necropsied the mice after 30 days of treatment.


Untreated 5-month-old del3-4 mice had serious liver disease with numerous cysts. Fig.1A illustrates this wide range of cyst sizes, with cysts that are very large in some parts of the liver, and in other parts, numerous but smaller. VX-809 had a profound effect in reducing cysts of all sizes, including the largest ones, as illustrated in Fig.1A&B. The summary data in Fig.1C show that VX-809 had profoundly reduced the larger cysts and was remarkedly effective in reducing even the smaller cysts. We stained liver sections in 5-week-old mice with Ki67, a marker of proliferation, and with CK19, a cholangiocyte marker. There was a substantially (~50-fold) higher percentage of del3-4 cells that were positively stained for both Ki67 and CK19, demonstrating that increased proliferation occurred within the bile duct. VX-809 reduced the staining by one-half. Further experimentation found using confocal microscopy that CFTR is located at the apical membrane in cholangiocytes from the del3-4 mice. VX-809 reduced the CFTR at the apical membrane but increased it at the basolateral membrane.


These data indicate that VX-809 reduces proliferation and the presence of CFTR at the apical membrane while increasing CFTR at the basolateral membrane. Demonstration of liver cyst reduction increases the therapeutic potential of VX-809 as a treatment of ARPKD.

Fig 1: Livers from Pkhd1del3-4/del3-4 (del3-4) mice A. Photos of livers. Please note the massive cysts in the untreated mice vs. lack of cysts in the treated mice. B. Pictures of H&E staining. C. Summary of cyst size. Note the reduction in cyst size following treatment with VX-809.


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