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Kidney Week

Abstract: PO1201

Modeling Gene-Targeted Strategies for Therapeutic Correction of PKD1 Loss-of-Function Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Trudel, Marie, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Kurbegovic, Almira, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Loayza-Vega, Kevin, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Pacis, Rey Christian, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Parrot, Camila, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada

Autosomal dominant polycystic kidney disease (ADPKD) causes cyst progression leading to renal failure, mainly by PKD1 mutations. Since microscopic cysts in ADPKD kidneys are likely formed in utero, we targeted at fetal stage wild type Pkd1/Pc1 protein in Pkd1-/- mouse from 3 series of transgenic (Tg) lines, to assess for long-term cure of severe cystogenesis and neonatal death.


Pc1 re-expression in Pkd1-/- mouse was targeted by 3 genetic matings: a) a systemic Pkd1TAG mouse b) 2 renal-specific SBPkd1TAG mice mild and high expressor (1 &10 Tg copies) c) a novel Tg line targeting Pkd1 cDNA with renal-specific elements, SBP (16 Tg copies). Longitudinal renal molecular (Q-PCR, IB), histologic (tubular origin IF, RNAScope) and survival analyses were performed.


Mice Pkd1TAG;Pkd1-/- expressing 7-fold over endogenous Pkd1 gene and intense signal over all tubular segments are totally rescued. Mice SBPkd1TAG;Pkd1-/- with mild (~0.64) Pc1 expression are not only rescued from neonatal death but renal cysts are delayed to P5 affecting mainly collecting tubules, causing death at P15, generating a 4-fold increased life expectancy. Mice SBPkd1TAG;Pkd1-/- with high (7-fold) Pc1 expression, initiate distal renal cysts at P15 and survive till ~4 mo with 25-fold increased life expectancy. Mice SBP;Pkd1-/-, with ~16 SBP copies expressed 0.87-fold the Pkd1 endogenous level, exhibit few renal cysts at P0 whereas at P5 are mainly of distal and collecting tubular origin and survived until P12-15. While SBP reached Pkd1 therapeutic levels similar to the mild SBPkd1TAG, the additional Tg copies suggest the presence of regulatory region within Pkd1 gene-body. Renal cysts in SBPkd1TAG;Pkd1-/- and SBP;Pkd1-/- co-detected by RNAScope and IF, arise likely from insufficient and chimeric Pkd1 re-expression. These analyses also shed light on Pkd1 spatio-temporal expression pattern with highest expression in collecting tubules during renal maturation that shifts to distal tubules following maturation.


Pkd1 is regulated by elements both upstream for spatio-temporal pattern and intragenic sequences for expression levels. The renal-specific SB minimal regulatory region is sufficient for therapeutic correction in one copy Tg. Our study demonstrates that Pc1 re-expression can substantially delay cystogenesis and markedly extend lifespan.


  • Government Support – Non-U.S.