Abstract
Tyrosinemia type 3, caused by a genetic deficiency of 4-hydroxyphenylpyruvic acid dioxygenase (HPD) in tyrosine catabolism, is characterized by convulsion, ataxia, and mental retardation. The III mouse is a model of tyrosinemia type 3. HPD activity and protein are defective in the liver and its blood tyrosine levels are elevated, the range being between 1,100 and 1,656 μM. We constructed a recombinant adenoviral vector bearing the human HPD cDNA (AdexCAGhHPD), which is expressed under the control of a potent CAG promoter. III mice were injected with 1.0 × 108 to 1.0 × 109 pfu of AdexCAGhHPD through the tail vein. When 3.0 × 108–1.0 × 109 pfu were injected, blood tyrosine levels decreased within 3 hr, reached a normal range (under 300 μM), and remained at a low level for 2–6 weeks. Hepatic HPD activities also increased as early as 3 hr after the injection of 5.0 × 108 pfu, reached the levels comparable to the control mice in 3–7 days, and then decreased, and correlated well to blood tyrosine. Hepatic HPD expression was confirmed by Northern blot and immunoblot analyses. Histology revealed no difference (gross or microscopic) between the liver injected with AdexCAGhHPD and the control. No significant changes in blood tyrosine levels were noted after the second injection of 5.0 × 108 pfu of AdexCAGhHPD. Thus, the intravenous administration of the adenoviral vector bearing a foreign gene seems suitable for transient, early gene transfer into the liver.
Overview summary
We constructed a recombinant adenoviral vector bearing human 4-hydroxyphenylpyruvate dioxygenase (HPD) cDNA, which is expressed under the control of a potent CAG promoter. In the experiments using a model for tyrosinemia type 3 lacking HPD protein, we found that intravenous administration of the adenoviral vector bearing a foreign gene is suitable for a transient, early gene transfer into the liver.
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