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Abstract: TH-PO404

Correction of PKD by Gene Transfer into Pkd1-Null Mouse Model

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 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

Autosomal dominant polycystic kidney disease(ADPKD) causes renal cysts and insufficiency due mainly to PKD1 mutations. Since microscopic cysts in ADPKD kidneys are likely formed in utero, we re-expressed wild-type Pkd1/Pc1 protein in Pkd1-/- mouse via germ line by series of complementary gene transfer to assess for long-term cure of severe cystogenesis and neonatal death.


Pc1 re-expression in the most severe mouse model Pkd1-/- was assessed by 3 strategies using genomic Pkd1 under its own regulatory elements (Pkd1wt), driven by kidney specific regulatory elements (900nt SB, SBPkd1) or Pkd1Minigene. Renal molecular (qPCR, IB), tubular (stainings, IF, RNAscope) and functional (BUN, hct) analyses were performed.


Pkd1-/- mice targeted with 2 distinct Pkd1wt gene transfers, of ~8-fold overexpression and intense RNAscope signal over all tubular segments and glomeruli similarly to endogenous cell profile, fully rescued PKD phenotype. SBPkd1 one- and high-copy gene transfers conveyed 0.6- or 7-fold Pkd1 endogenous levels respectively. One-copy SBPkd1 transfer initiates cysts after birth ~P3 and confer sufficient Pkd1 expression during maturation to correct proximal tubules and glomeruli, to minimize distal cyst and to postpone but not prevent cyst in collecting ducts. This transfer extended Pkd1-/- life survival by 4-fold. High-copy SBPkd1 transfer provide proper targeting and expression levels for complete rescue during renal maturation, and significantly retard cyst in proximal and collecting tubules at post-maturation but is insufficient to prevent distal cysts. This transfer increased lifespan by 25-fold. SBPkd1 transfers show that collecting tubules require higher Pkd1 expression during maturation and that SB regulatory elements appreciably overlap with those of the endogenous promoter. High-copy renal Pkd1Mini transfer resulted in similar expression to endogenous Pkd1 with widespread and homogeneous weak Pkd1 cellular signal, partially rescuing glomeruli and all cystic tubular segments during maturation and attained therapeutic levels with increased lifespan by 4-fold.


Our study determined that Pkd1 intragenic sequences not only control levels of expression but alike the upstream sequences, also regulate spatio-temporal expression pattern. One-copy SBPkd1 is sufficient to substantially delay cystogenesis. Pc1 re-expression can considerably extend lifespan or eliminate PKD.


  • Government Support – Non-U.S.