Targeting Transgene Expression for Cystic Fibrosis Gene Therapy
| Autor: | Jim Hu, Gregory P. Downey, Rosetta Belcastro, Brent Steer, David R. Koehler, Martin Post, Yanxia Wen, Vicky Hannam, A. Keith Tanswell |
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| Rok vydání: | 2001 |
| Předmět: |
Cystic Fibrosis
Transgene Genetic enhancement Genetic Vectors Gene Expression Mice Inbred Strains Glycerophospholipids Biology Cystic fibrosis Alveolar cells Mice Surface-Active Agents 03 medical and health sciences 0302 clinical medicine Drug Discovery Gene expression Genetics medicine Animals Humans Tissue Distribution Transgenes Molecular Biology 030304 developmental biology Pharmacology Submucosal glands 0303 health sciences Expression vector Phosphatidylethanolamines Gene Transfer Techniques Genetic Therapy respiratory system medicine.disease Molecular biology 3. Good health Quaternary Ammonium Compounds medicine.anatomical_structure Lac Operon Organ Specificity 030220 oncology & carcinogenesis Injections Intravenous Liposomes Keratins Molecular Medicine Expression cassette |
| Zdroj: | Molecular Therapy. 4:58-65 |
| ISSN: | 1525-0016 |
| DOI: | 10.1006/mthe.2001.0412 |
| Popis: | We have developed an expression cassette for cystic fibrosis (CF) gene therapy using control elements from the human cytokeratin 18 gene (KRT18, also known as K18). KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF. We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues. We found expression in nasal and bronchial epithelium, airway submucosal glands, gall bladder, and kidneys. Expression was low in pancreas and gut, and absent from liver and alveolar lung. This is consistent with the expression pattern reported for a K18lacZ transgenic mouse. Following delivery of a cytomegalovirus (CMV) major immediate-early promoter/enhancer-driven lacZ plasmid, we found expression in bronchi, submucosal glands, alveolar cells, liver, and kidney. We did not detect expression in nose, pancreas, gall bladder, or gut. Using fluorescently labeled plasmid delivered by means of liposomes, we identified the liver, alveolar lung, and kidneys as the major plasmid deposition sites. Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA. A KRT18-based vector may be a useful alternative to viral promoter-based vectors in clinical gene therapy trials to treat CF. |
| Databáze: | OpenAIRE |
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