Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Polycystic kidney disease (PKD) is a genetic renal disease characterized by the development of renal fluid-filled cysts, which eventually leads to kidney failure. There are two types of polycystic kidney disease: Autosomal Dominant Polycystic Kidney Disease (ADPKD), the more common form, and Autosomal Recessive Polycystic Kidney Disease (ARPKD), which is much rarer. ADPKD is the most common inherited disorder that typically presents in adults. It is mostly caused by mutations of the PKD1 gene encoding polycystin 1 (PC1), which regulates cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion.

Tolvaptan has recently been approved as a clinical drug that slows ADPKD progression, potentially through increasing urination and avoiding fluid reabsorption in cysts. Emerging gene therapies have also offered the promise of a complete cure against ADPKD.

To accelerate the research and development of these new treatments, GemPharmatech has developed an ADPKD model (Pkd1 flox/flox, Cdh16-CreER^T2), in which mouse Pkd1 is conditionally abolished in the tubule epithelium of 3- to 4-week-old mice. These mice exhibited renal disorders, enlarged kidney volume and development of cyst structures after induction, which can be partially relieved by Tolvaptan treatment.

Sample Phenotypic Data

● Body weight change

One hundred mg/kg/d tamoxifen was injected into 3-week-old mice, with the first injection denoted as Day 1. In male Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice, a decrease in body weight was observed starting from Day 63. N=3.

● Serum BUN and CREA

Serum BUN and CREA level were significantly increased in male Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice, indicating impaired kidney function. N=3

● Renal ultrasonography

Renal volume was significantly increased in female Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice. N=3

● Kidney Cystic Index of Day92 mice

Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice displayed significant increase in kidney cystic index. N=3

● Kidney pathology analysis by HE staining

Significant pathology phenotypes, including the presence of multiple cysts, protein casts and tubular atrophy were observed in Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice.

Sample Efficacy Data

● Study Design

● Serum BUN and CREA

At Day 86 and Day 100, 0.1% tolvaptan treatment significantly attenuated the increase of serum BUN and CREA levels in male Pkd1: fl/fl Cdh16-CreER^T2: ki/wt model mice. N=5

● Renal ultrasonography-male

At Day 80 and Day 92, compared to Pkd1: fl/fl Cdh16-CreER^T2: wt/wt mice, renal volumes were significantly increased in Pkd1: fl/fl Cdh16-CreER^T2: ki/wt male mice. 0.1% tolvaptan treatment partially reversed the expansion of kidney volume. N=5

● Renal ultrasonography-female

At Day 65, Day 80 and Day 92, compared to Pkd1: fl/fl Cdh16-CreER^T2: wt/wt mice, renal volumes were significantly increased in Pkd1: fl/fl Cdh16-CreER^T2: ki/wt male mice. 0.1% tolvaptan treatment partially reversed the expansion of kidney volume at Day 92. N=5

● Kidney index of Day103 male mice and Day107 female mice

Treatment with 0.1% tolvaptan attenuated the increase of kidney index in Pkd1: fl/fl Cdh16-CreER^T2: wt/wt mice. N=5