Therapeutic targets for ADPKD

In ADPKD, mutations in the PKD1 or PKD2 gene cause changes in polycystin 1 or 2 (PC1 and PC2) expression, which in turn interferes with several intracellular signaling pathways that are e.g., involved in cell proliferation, fluid secretion, and ciliary function. The complex network of signaling pathways that are dysregulated in cystic kidneys of ADPKD patients provides many potential therapeutic targets for ADPKD treatment (Figure 1). 

Due to its genetic and phenotypic similarity to ADPKD patients, InnoSer’s ADPKD mouse model can be used to test the efficacy of new therapeutic targets for ADPKD from gene therapy to targeting of the involved pathological processes and pathways (e.g., AMPK). The ADPKD model’s pathophysiology involves abnormal proliferation (Figure 2), development of fibrosis (Figure 3), and low-grade inflammation (as reported by others using our model: Dagorn et al., 2023). Disease progression can be finetuned based on customer needs due to the conditional (tamoxifen-induced) knockout of the Pkd1 gene, which results in key pathophysiological features observed in ADPKD patients. More information about the differences between the models created by the timing of disease induction can be found in our blog post here.  

At InnoSer, our ADPKD platform supports the testing of multiple therapeutic approaches, including small molecules, antibody-based therapeutics, and gene therapies. InnoSer’s ADPKD model is also suitable to test already existing drugs, as drug repurposing may arise as a promising strategy for approval of ADPKD treatment given ADPKD’s rare disease status.  

Multiple drugs currently indicated for drug re-purposing in the literature have been validated as positive controls at InnoSer: mTOR inhibitors (Everolimus, Rapamycin), vasopressin receptor antagonists (Mozavaptan, Tolvaptan; only approved ADPKD treatment), and AMPK activators (Salsalate; view validation data in our previous blog posts here and here). Thus, depending on your test item’s mechanism of action, different suitable positive controls may be used e.g., for compounds targeting upstream or downstream targets of the AMPK signaling pathway, Salsalate may be a suitable positive control.  

FIGURE 1. Overview of ADPKD pathophysiology and main putative therapeutic targets for ADPKD potential treatments. Full summary of targets is further detailed in a review paper of Zhou and al. (2023).

FIGURE 2. InnoSer’s ADPKD model enables detailed analyses of the cystogenesis process (proliferation) offering robust insights into the therapeutic efficacy of compounds targeting upstream and/or downstream pathways involved in cyst growth and cell proliferation. (A) In the P10 mouse model of ADPKD (kidneys obtained at PND27), Ki67-positive nuclei are observed, indicating early proliferation and cyst formation in the kidneys. (B) In the P18 mouse model of ADPKD (kidneys obtained at PND115), Ki67 staining shows expanded areas of proliferation, reflecting the progression of cystic expansion.  

FIGURE 3. InnoSer’s ADPKD model enables detailed analysis of fibrosis, supported by various histopathological assessments to assess the efficacy of potential treatments that may mitigate fibrotic tissue development. (A) Masson’s trichrome staining in the P10 ADPKD mouse model (kidneys obtained at PND27) demonstrates mild fibrotic changes around cysts, highlighting early-stage scarring within the renal tissue. (B) In the P18 ADPKD mouse model (kidneys obtained at PND115), the staining reveals a progression in fibrotic changes, representing more advanced stages of the disease.   

InnoSer’s ADPKD model allows for detailed analysis across multiple disease pathways, thanks to our expanded biomarker staining capabilities. Below are some of the key histopathology markers available within our ADPKD disease platform: 

• Apoptosis (for e.g., Caspase-3, Bcl-2) 

• Fibrosis (for e.g., trichrome, picosirius red)  

• Renal injuries (Lcn2) 

• Macrophage infiltration (CCL2)  

• Cyst growth (Cyclin D) and cyst compression (KIM1)  

• Myofibroblasts (alpha-SMA) 

Interested in performing efficacy studies using InnoSer’s ADPKD mouse model? Consulting with our nephrology study experts will allow you to carry out tailored studies while collecting the most study-appropriate data. We also advise you on the most optimal model selection and study design set-up, considering your budget and study timelines to enable you with the most cost-effective solution without sacrificing any important research insights.  

Interested in performing efficacy studies using other mouse models of kidney disease? Our extensive nephrology model expertise and readout capabilities (ultrasound imaging, urine analysis, transdermal GFR, blood urea nitrogen and/or creatinine assessments) allow us to support various nephrology models indications with experience in SLE, diabetic kidney disease, and kidney ischemia-reperfusion.