Modeling gene-targeted strategies for correction of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) causes renal cysts and leads to end-stage renal disease in midlife due mainly to gene mutations. Virtually no studies have explored gene therapeutic strategies for long-term effective treatment of PKD. Toward this aim, the severely cystic -null mouse model was targeted with a series of transgene transfers using genomic under its regulatory elements (), a kidney-targeted gene (), or . The introduced gene constructs with ∼8-fold overexpression display similar endogenous cellular profiles and full complementation of phenotype and establish the referral genomic length for proper regulation. transgene transfer expressing 0.6- or 7-fold 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 promoter/5' UTR regulation. Renal-targeted at high copy numbers conveys an expression level similar to that of the endogenous gene, with widespread and homogeneous weak cellular signal, partially rescuing all cystic tubular segments. These transgene transfers determine that intragenic sequences regulate not only expression levels but also spatiotemporal patterns. Importantly, our study demonstrates that re-expression from hybrid therapeutic constructs can ameliorate, with considerably extended lifespan, or eliminate PKD.