Modeling Pkd1 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 PKD1 gene mutations. Virtually no studies have explored gene therapeutic strategies for long-term effective treatment of PKD. Toward this aim, the severely cystic Pkd...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000529 |
| _version_ | 1827929119761891328 |
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| author | Almira Kurbegovic Rey Christian Pacis Marie Trudel |
| author_facet | Almira Kurbegovic Rey Christian Pacis Marie Trudel |
| author_sort | Almira Kurbegovic |
| collection | DOAJ |
| description | 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 (Pkd1wt), a kidney-targeted Pkd1 gene (SBPkd1), or Pkd1Minigene. The introduced Pkd1wt 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. SBPkd1 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 Pkd1Minigene 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. |
| first_indexed | 2024-03-13T06:18:21Z |
| format | Article |
| id | doaj.art-1ef90b1e73d44b9a81a57cf4168e4457 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-13T06:18:21Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-1ef90b1e73d44b9a81a57cf4168e44572023-06-10T04:27:46ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-06-0129366380Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney diseaseAlmira Kurbegovic0Rey Christian Pacis1Marie Trudel2Institut de Recherches Cliniques de Montréal, Faculté de, Médecine, Montreal, QC, CanadaInstitut de Recherches Cliniques de Montréal, Faculté de, Médecine, Montreal, QC, CanadaInstitut de Recherches Cliniques de Montréal, Faculté de, Médecine, Montreal, QC, Canada; Corresponding author: Marie Trudel, Molecular Genetics and Development, IRCM, 110 Avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada.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 (Pkd1wt), a kidney-targeted Pkd1 gene (SBPkd1), or Pkd1Minigene. The introduced Pkd1wt 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. SBPkd1 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 Pkd1Minigene 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.http://www.sciencedirect.com/science/article/pii/S2329050123000529Pkd1 gene therapyPkd1 locus/minigenepolycystic kidney diseasePKD transcriptional regulationsmall SB renal cassettePkd1 RNAscope |
| spellingShingle | Almira Kurbegovic Rey Christian Pacis Marie Trudel Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease Molecular Therapy: Methods & Clinical Development Pkd1 gene therapy Pkd1 locus/minigene polycystic kidney disease PKD transcriptional regulation small SB renal cassette Pkd1 RNAscope |
| title | Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease |
| title_full | Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease |
| title_fullStr | Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease |
| title_full_unstemmed | Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease |
| title_short | Modeling Pkd1 gene-targeted strategies for correction of polycystic kidney disease |
| title_sort | modeling pkd1 gene targeted strategies for correction of polycystic kidney disease |
| topic | Pkd1 gene therapy Pkd1 locus/minigene polycystic kidney disease PKD transcriptional regulation small SB renal cassette Pkd1 RNAscope |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000529 |
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