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Genetic manipulation of sinusoidal endothelial cells.
- Source :
-
Journal of gastroenterology and hepatology [J Gastroenterol Hepatol] 2007 Jun; Vol. 22 Suppl 1, pp. S68-72. - Publication Year :
- 2007
-
Abstract
- Altered gene expression in liver sinusoidal endothelial cells (SEC) is associated with a variety of aspects of liver pathophysiology. It is, therefore, possible to envision a new therapeutic strategy for treatment of intractable liver diseases and achievement of graft-specific immunotolerance through modulation of SEC functions by genetic engineering. The SEC possesses unique hyaluronan receptors that recognize and internalize hyaluronic acid (HA). This characteristic was used in the development of a system for targeting foreign DNA to SEC. A gene carrier system was prepared by coupling HA oligomers to poly L-lysine (PLL) in a 1:1 weight ratio by reductive amination reaction. The resulting copolymer (PLL-g-HA) was mixed with various amounts of DNA in 154 mM NaCl. Inter-polyelectrolyte complex formation between PLL-g-HA and DNA exhibited minimal self-aggregation, explaining the highly soluble nature of the complex. Complex formation between PLL-g-HA and DNA was further assessed with a gel retardation assay. The titration point representing the minimum proportion of PLL-g-HA required to retard the DNA completely occurred at a 1:1 copolymer (based on PLL) to DNA charge ratio. Following intravenous injection of (32)P-labeled pSV beta-Gal plasmid complexed to PLL-g-HA in Wistar rats, >90% of the injected counts were shown to be taken up by the liver. Further, it was shown that the PLL-g-HA/DNA complex was distributed exclusively in the SEC. At 72 h after injection of 90 mug of pSV beta-Gal in a PLL-g-HA-complexed form, a large number of SEC expressing beta-galactosidase were detected. So, the PLL-g-HA/DNA system permits targeted delivery of exogenous nucleotide agents selectively to the liver SEC, providing a novel strategy for manipulation of SEC functions.
- Subjects :
- Animals
DNA chemistry
DNA genetics
Endothelium cytology
Endothelium metabolism
Gene Expression
Genetic Therapy
Liver blood supply
Microcirculation
Polylysine analogs & derivatives
Polylysine chemical synthesis
Polylysine chemistry
Polylysine metabolism
Polymers
Rats
Transfection
DNA metabolism
Gene Transfer Techniques
Hyaluronic Acid analogs & derivatives
Hyaluronic Acid chemical synthesis
Hyaluronic Acid chemistry
Hyaluronic Acid metabolism
Liver cytology
Liver metabolism
Liver Diseases physiopathology
Liver Diseases therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0815-9319
- Volume :
- 22 Suppl 1
- Database :
- MEDLINE
- Journal :
- Journal of gastroenterology and hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 17567471
- Full Text :
- https://doi.org/10.1111/j.1440-1746.2006.04657.x