PAPPA is an enzyme that releases insulin-like growth factor 1 and is overexpressed in polycystic kidneys. Researchers generated two human antibodies against it and tested them in mouse models: male jck mice with advanced disease treated from 6 to 12 weeks, and male and female Pkd1 RC/RC mice with early disease treated from 4 to 16 weeks.
Both antibodies blocked PAPPA-mediated cleavage of the binding proteins, and every dose tested in male mice showed good target engagement and reduced cystic disease, inflammation and fibrosis, with lower IGF1 receptor signalling. Protection was weaker in female than in male mice. The new antibodies compared favourably with an earlier mouse antibody.
These are animal data. The authors note that long-term safety and the sex difference in response should be considered in trial design. Nothing here is ready for patients with autosomal dominant polycystic kidney disease.
- No clinical action follows from this preclinical study
- Current treatment for polycystic kidney disease, including blood pressure control and tolvaptan where indicated, is unchanged
- Watch for first-in-human data before discussing this approach with patients
- The weaker response in female mice is a reminder to include both sexes in future trials
Why it matters
Therapies for the commonest genetic kidney disease remain limited, and new targets matter.
Don't overread it
Mouse efficacy often fails to translate, and no human or safety data are reported.
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