Regulatory elements for delivery to the liver
The invention is directed to novel combinations of liver specific enhancers and promoter elements for achieving persistent transgene expression in the liver. The liver specific enhancer elements may be derived from either the human serum albumin, prothrombin, α-1microglobulin or aldolase genes in single copies or in multimerized form linked to elements derived from the cytomegalovirus intermediate early (CMV), α-1-antitrypsin or albumin promoters. In a preferred embodiment of the invention, an adenoviral vector comprising a liver specific enhancer/promoter combination operably linked to a transgene is administered to recipient cells. In other embodiments of the invention, adeno-associated viral vectors, retroviral vectors, lentiviral vectors or a plasmid comprising the liver specific enhancer/promoter combination linked to a transgene is administered to recipient cells. Also within the scope of the invention are promoter elements derived from the human prothrombin gene and the β-fibrinogen gene.
1. A recombinant DNA vector, comprising a human serum albumin promoter and two human prothrombin enhancers.
2. The recombinant DNA vector according to claim 1 , further comprising a coding DNA sequence operativelv linked to said promoter and enhancers.
3. A recombinant DNA vector, comprising an α-1-antitrypsin promoter and two human prothrombin enhancers.
4. The recombinant DNA vector according to claim 3 , further comprising a coding DNA sequence operatively linked to said promoter and enhancers.
5. A recombinant DNA vector, comprising an α-1-antitrypsin promoter and two α-1 microglobulin (A1MB) enhancers.
6. The recombinant DNA vector according to claim 5 , further comprising a coding DNA sequence operatively linked to said promoter and enhancers.
7. A recombinant adenoviral vector comprising the recombinant DNA vector of claims 1 , 3 , or 5 .
8. The recombinant adenoviral vector of claim 7 wherein said recombinant DNA vector further comprises a coding DNA sequence operatively linked to said promoter and enhancers.
9. A recombinant adeno-associated viral vector comprising the recombinant DNA vector of claims 1 , 3 , or 5 .
10. The adeno-associated viral vector of claim 9 wherein said recombinant DNA vector further comprises a coding DNA sequence operatively linked to said promoter and enhancers.
11. The recombinant DNA vector according to any one of claims 2 - 6 , wherein the coding DNA sequence is alpha-galactosidase.