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Nucleic acid constructs, cells transformed therewith and methods utilizing same for inducing liver regeneration and alleviation of portal hypertension

a technology of nucleic acid and constructs, which is applied in the field of nucleic acid constructs, can solve the problems of high blood vessel pressure, patients subject to inborn metabolic abnormalities, and inability of diseased organs to perform vital functions, etc., and achieve the effects of reducing the risk of liver cirrhosis

Inactive Publication Date: 2002-11-07
MULTI GENE VASCULAR SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The diseased organ may be unable to perform vital functions such as manufacturing proteins and removing harmful substances from the blood.
The affected liver tissue may block the flow of blood, causing high pressure in blood vessels, which serve the liver (portal hypertension).
In addition, patients subject to inborn metabolic abnormalities may be at risk for developing liver cirrhosis.
Although liver transplants can reestablish normal liver function such procedures are complex and as such only successful in a fraction of the cases.
In addition, constant shortage of organs suitable for transplantation further limits application of this procedure.
Thus, current treatment regimens for cirrhosis-related liver damage provide solutions for some of the complications accompanying cirrhosis while being useless in inducing liver repair and regeneration.
Current treatment methods for cirrhosis-related liver damage offer solutions for only some of the complications resulting from liver damage while being ineffective in reversing liver damage and restoring normal liver function.

Method used

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  • Nucleic acid constructs, cells transformed therewith and methods utilizing same for inducing liver regeneration and alleviation of portal hypertension
  • Nucleic acid constructs, cells transformed therewith and methods utilizing same for inducing liver regeneration and alleviation of portal hypertension
  • Nucleic acid constructs, cells transformed therewith and methods utilizing same for inducing liver regeneration and alleviation of portal hypertension

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation and Expression Analysis of Adenoviral Vectors Expressing the VEGF.sub.165 cDNA, HGF cDNA and the bacterial .beta. galactosidase gene

[0126] Recombinant adenoviral vectors expressing either bacterial Lac Z (.beta.-galactosidase) (Weisz et al, Circulation 2001, in press), human VEGF.sub.165 gene (Genbank Accession number AB021221) or human HGF gene (Genbank Accession number M29145) (rAdLacZ, rAdVEGF, respectively) were constructed using commonly practiced molecular cloning techniques.

[0127] To construct the bacterial .beta.-galactosidase expressing plasmid, a 3700 bp HindIII-BamHI .beta.-galactosidase DNA fragment was inserted into pCA3 (Weisz et al, Circulation 2001, in press) under the control of a CMV promoter. A 600 bp BamHI DNA fragment containing the human VEGF.sub.165 cDNA (gift of Dr. J. Abraham), including the secretion signal sequence was similarly inserted into pCA3.

[0128] The pCA3 plasmids containing either the VEGF.sub.165 or the .beta. galactosidase genes, wer...

example 2

Generation and Analysis of Model Animals Suffering from Liver Cirrhosis

[0139] Cirrhosis Induction in Rats

[0140] Carbon tetrachloride (CCl1) treatment was used to induce cirrhosis in Sprague-Dawley rats, which served as a first group of model animals. Twenty doses of CCl1 [50% (vol / vol) solution in mineral oil, 0.5 ml / kg body weight] were administered intra muscularly (i.m.) into the gluteal region every 5 days. A sodium phenobarbitone solution (500 mg / L in drinking water) was administered for 7 days prior to and during this CCl1 treatment (FIGS. 2a-3).

[0141] Liver tissue from the treated animal was excised and fixated in buffered formaldehyde (McLean E. K., et al, 1969; Proctor E. et al, 1982) and the presence and degree of cirrhosis in the liver tissue was determined by histopathological examination (FIG. 4a-c).

[0142] Portal Vein Pressures Analysis:

[0143] Treated animals were anesthetized via i.m. administration of 30 mg / kg ketamine and 2 mg / kg xylazine. Following anesthesia, the a...

example 3

Transformed Cell Analysis

[0159] Effect of VEGF Gene Transfer on Endothelial Cell & Smooth Muscle Cell Proliferation

[0160] HSVEC (Human saphenous vein endothelial cells, Weisz et al, Circulation 2001 in press) cells infected with the rAdVEGF expression vector described hereinabove (10.sup.3 pfu per cell) exhibited an increased cell proliferation rate as compared to rAdLacZ infected control cells and uninfected cell (FIG. 13a).

[0161] In contrast, rAdVEGF infection had no effect on the proliferation rate of HSVSMC (Human saphenous vein smooth muscle cells, Weisz et al, Circulation 2001 in press) as compared to control cells (FIG. 13b).

[0162] Similar results were obtained using the BrdU nucleotide analog incorporation method (Weisz et al., 2000). BrdU positive HSVEC and HSVSMC cells were counted five days following infection with the adenoviral vectors described above. Counting was effected using antibodies specific against the nucleotide analog. A significant increase in BrdU positive ...

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Abstract

A method of inducing liver regeneration in a damaged liver tissue region of an individual is provided. The method including the step of providing at least two distinct growth factors to the damaged liver tissue region of the individual, at least one of the at least two distinct growth factors being an angiogenic factor.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001] The present invention relates to nucleic acid constructs, cells transformed therewith and methods of utilizing such constructs and transformed cells for inducing hepatocytes proliferation and liver regeneration.[0002] Liver Cirrhosis[0003] Cirrhosis, is a disease of the liver, which results from injury to liver tissue. Cirrhosis is characterized by scar tissue formation throughout the organ; groups of cells termed regenerative nodules, surrounded by sheets of scar tissue, replace the normal spongy tissue of the liver. The diseased organ may be unable to perform vital functions such as manufacturing proteins and removing harmful substances from the blood. The affected liver tissue may block the flow of blood, causing high pressure in blood vessels, which serve the liver (portal hypertension). This blockage can lead to gastro-esophageal bleeding and ascites and in addition can contribute to the development of encephalopathy.[0004] Liver inju...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61F2/958A61K38/00A61K38/18A61K38/19C07K14/47
CPCA61K38/1825A61K38/1833C12N2740/13043C12N2710/10343A61K48/005A61K38/1866A61K38/1858C12N2799/027C12N2799/022A61M25/10A61M2025/1052C07K14/47A61K2300/00A61P1/16
Inventor FLUGELMAN, MOSHE Y.OTT, MICHAEL
Owner MULTI GENE VASCULAR SYST
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