A significant challenge in the ADPKD research field is demonstrating efficacy of novel compounds in preclinical research models using clinically relevant endpoints. To date, total kidney volume (TKV) is the only FDA and EMA-approved imaging biomarker that is used as a surrogate endpoint to quantify efficacy of novel compounds on the severity of ADPKD in clinical trials.  

To ensure clinical relevance early on in your drug development pipeline, InnoSer can perform ultrasound measurements to assess TKV in the ADPKD mouse model (Figure 1). Another highly clinically relevant marker which has been shown to correlate with TKV in humans, is glomerular filtration rate (GFR). GFR can be measured in the ADPKD mouse model transdermally. 

In one of our recent newsletters, we also highlighted cystic index as one of the possible histopathology assessments performed by our in-house veterinary pathologist. Depending on the mechanism of action of your compound, other biomarkers of kidney health can be explored such as inflammation, fibrosis, tubular casts, glomerular atrophy and tubular dilation (Figure 2).  

In addition to our expertise in ADPKD, our team frequently performs studies using chemically induced type 1 diabetic models, which develops signs of diabetic kidney disease complications over time (Figure 3).   

FIGURE 1. Assessment of kidney volume by ultrasound allows the determination of disease progression and compound efficacy in the mouse model of ADPKD. Compared to healthy controls, the kidney volume of ADPKD mice is significantly increased over time, indicating decline in renal health. Right kidney volume is significantly lower in the 0,1% Tolvaptan (used as positive control) and compound Y (test compound) groups compared to the vehicle control group (Mean ± SEM; one-way ANOVA; **P<0.01, ***P<0.001) Proprietary data.  

FIGURE 2. Histopathological scoring provides more insights on the mechanism of action of test compound. (A) Compared to vehicle control mice, ADPKD mice treated with 0.1% Tolvaptan show significantly lower tubular dilation (Mean ± SEM; Mann-Whitney U test; *P<0.05). (B) Tubules of ADPKD mice have a very thin attenuated wall (yellow arrows). (C) Compared with untreated ADPKD mice, Tolvaptan–treated mice show significantly less atrophied glomeruli (Mean ± SEM; Mann-Whitney U test; *P<0.05). (D) ADPKD mice show atrophied nuclei and degenerated glomeruli (yellow arrows).  

FIGURE 3. Following chemical T1D diabetes induction (Alloxan), signs of development of early diabetic kidney disease such as distorted and enlarged glomeruli become apparent compared to normal healthy (control) conditions.  

Drug development can be an iterative and long process, whereby InnoSer can be your dedicated partner, offering fast turnaround times with back-to-back experiments to help you optimise your lead compounds. Curious to learn more about InnoSer’s capabilities within the drug development space? View our Discovery and Development CRO Services here.