Analysis of Metabolic and Gene Expression Changes after Hydrodynamic DNA Injection into Mouse Liver

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  • Herrero Maria Jose
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia
  • Monleon Daniel
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia
  • Morales Jose Manuel
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia
  • Mata Manuel
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia
  • Serna Eva
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia
  • Aliño Salvador Francisco
    Gene Therapy Unit, Department of Pharmacology. Faculty of Medicine, University of Valencia

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The hydrodynamic injection in mice tail vein of a plasmid (40 μg DNA) bearing the human α1-antitrypsin gene mediates: a) good liver gene transfer resulting in therapeutic plasma levels of human protein (1 mg/ml, approximately) from days 1—10 after injection; b) low liver injury as demonstrated by a poor and transient increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) in mouse plasma; 3) limited expression and metabolic changes in host liver genes and metabolites as evaluated on days 2 and 10 after injection. Groups of three mice were uninjected (control) or hydrodynamically injected with saline or plasmid DNA and then sacrificed on days 2 and 10 after injection. The results of principal component analysis (PCA) show, both in expression microarray and metabolomic anaylisis, that changes between control and hydrodinamically injected groups are not dramatic and tend to normalize after 10 d. The differences are even smaller between DNA and saline hydrodinamically injected mice. Hydrodynamic injection induces a complex but limited gene expression and metabolic change which includes variations in molecules related to energy metabolism and stress response. The results contribute to support that hydrodynamic method is a safe procedure of liver gene transfer but the long-term effect of hydrodynamic gene transfer procedure, remains to be studied.

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