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RECOMBENT VIRAL AND NON-VIRAL VECTORS CONTAINING THE HUMAN UROKINASE PLASMINOGEN ACTIVATOR GENE AND ITS UTILIZATION IN THE TREATMENT OF VARIOUS TYPES OF HEPATIC RENAL, PULMONARY, PANCREATIC AND CARDIAC FIBROSIS AND HYPERTROPHIC SCARS
RECOMBENT VIRAL AND NON-VIRAL VECTORS CONTAINING THE HUMAN UROKINASE PLASMINOGEN ACTIVATOR GENE AND ITS UTILIZATION IN THE TREATMENT OF VARIOUS TYPES OF HEPATIC RENAL, PULMONARY, PANCREATIC AND CARDIAC FIBROSIS AND HYPERTROPHIC SCARS
Hepatic cirrhosis is considered a severe health problemin Mexico, since it is the third mortality cause inworking-age people and there is no 100% effectivetreatment. Cirrhosis is characterized by an exacerbatedincrease of collagen in liver parenchyma, replacing thehepatocytes and thus provoking liver failure. This is oneof the reasons why we have used a gene therapy throughspecific delivery to cirrhotic livers of the gene ofhuman urokinase plasminogen activator (huPA), whichactivates mechanisms that induce the degradation ofexcess cellular matrix and stimulate hepatocyteproliferation, obtaining thus a fast re-establishment ofthe liver function. In the instant invention, themodified human uPA gene was inserted in the adenoviralvector (pAd-.DELTA.huPA), because it is not secreted and doesnot provoke hypercoagulation or spontaneous internalbleedings. Moreover, data from the bio-distribution essaywith an adenoviral vector with reporter gene .beta.-gal haveshown liver specificity as the target organ of thevector. Using ELISA, huPa protein was detected in liverhomogenates (4500 pg/ml) in animals treated withpAd--.DELTA.huPA and was also intracellularly detected throughimmunochemistry in liver cuts (80% positive cells). huPainduced a dramatic fibrosis reduction (85%) on day 10 ofvector administration, compared to control cirrhotic ratsand 55% hepatocyte proliferation increase. Liver functiontests (ALT, AST, alkaline phosphatase and bilirubin)dropped to nearly normal levels and hepatocyteproliferation was observed. Because of the two beneficialevent cascades, gene therapy with modified huPA can bedeveloped as a definite potential treatment for patientswith liver cirrhosis.
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