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Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease
Almira Kurbegovic1, Rey Christian Pacis1, Marie Trudel1
1Institut de Recherches Cliniques de Montréal, Faculté de, Médecine, Montreal, QC, Canada.
Insights
Gene therapy using Pkd1 gene constructs effectively treated polycystic kidney disease (PKD) in mice. This approach corrected kidney cysts and significantly extended lifespan, offering a promising therapeutic strategy for PKD.
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by renal cysts, often leading to end-stage renal disease.
- Mutations in the PKD1 gene are the primary cause of ADPKD.
- Effective long-term gene therapeutic strategies for PKD remain largely unexplored.
Purpose of the Study:
- To investigate the potential of gene therapy for treating polycystic kidney disease (PKD).
- To evaluate the efficacy of different Pkd1 gene constructs in a mouse model of severe PKD.
- To determine the impact of Pkd1 re-expression on cyst formation and lifespan.
Main Methods:
- Utilized a severely cystic Pkd1-null mouse model for gene therapeutic interventions.
- Administered transgene transfers of genomic Pkd1 (Pkd1^G), kidney-targeted Pkd1 (TnPkd1), and Pkd1^G.
- Analyzed Pkd1 expression levels, cellular profiles, cyst correction, and lifespan.
Main Results:
- Pkd1^G constructs with high overexpression (approx. 8-fold) fully complemented the Pkd1-/- phenotype.
- TnPkd1 transgene transfer (0.6- or 7-fold endogenous levels) corrected glomerular and proximal tubular cysts and delayed other tubular cysts.
- Renal-targeted Pkd1^G partially rescued all cystic tubular segments, indicating regulation by intragenic sequences.
Conclusions:
- Re-expression of the Pkd1 gene using therapeutic constructs can ameliorate PKD.
- Gene therapy significantly extended the lifespan of treated mice.
- Pkd1 intragenic sequences play a crucial role in regulating gene expression levels and spatiotemporal patterns, essential for therapeutic development.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) causes renal cysts and leads to end-stage renal disease in midlife due mainly to PKD1 gene mutations. Virtually no studies have explored gene therapeutic strategies for long-term effective treatment of PKD. Toward this aim, the severely cystic Pkd1-null mouse model was targeted with a series of transgene transfers using genomic Pkd1 under its regulatory elements (Pkd1), a kidney-targeted Pkd1 gene (Pkd1), or Pkd1. The introduced Pkd1 gene constructs with ∼8-fold overexpression display similar endogenous cellular profiles and full complementation of Pkd1-/- phenotype and establish the referral Pkd1 genomic length for proper regulation. Pkd1 transgene transfer expressing 0.6- or 7-fold Pkd1 endogenous levels is sufficient to correct glomerular and proximal tubular cysts and to markedly postpone cysts in other tubular segments as well, showing that the small SB elements appreciably overlap with Pkd1 promoter/5' UTR regulation. Renal-targeted Pkd1 at high copy numbers conveys an expression level similar to that of the endogenous Pkd1 gene, with widespread and homogeneous weak Pkd1 cellular signal, partially rescuing all cystic tubular segments. These transgene transfers determine that Pkd1 intragenic sequences regulate not only expression levels but also spatiotemporal patterns. Importantly, our study demonstrates that Pkd1 re-expression from hybrid therapeutic constructs can ameliorate, with considerably extended lifespan, or eliminate PKD.
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