Materials and Methods for Prevention and Treatment of RNA Viral Diseases
The subject invention concerns a method of inhibiting an RNA virus infection within a patient by increasing the amount of 2-5 oligoadenylate synthetase (2-5 AS) activity within the patient. Preferably, the preventative and therapeutic methods of the present invention involve administering a nucleotide encoding 2-5 AS, or at least one catalytically active fragment thereof, such as the p40, p69, p100 subunits, to a patient in need thereof. The present inventors have determined that overexpression of 2-5AS causes a reduction in epithelial cell damage, reduction in infiltration of mononuclear cells in the peribronchiolar and perivascular regions, and reduction in thickening of the septa in the lungs. Levels of chemokines, such as MIP1-α, are also reduced upon overexpression of 2-5AS. The subject invention also pertains to pharmaceutical compositions containing a nucleotide sequence encoding 2-5 AS and a pharmaceutically acceptable carrier, as well as vectors for delivery of the 2-5 AS nucleotide sequence.
1 . A pharmaceutical composition comprising a nucleotide sequence encoding a 2′-5′ oligoadenylate synthetase, or at least one catalytically active fragment thereof, and a pharmaceutically acceptable carrier.
2 . The pharmaceutical composition of claim 1 , wherein said composition further comprises an anti-viral agent.
3 . The pharmaceutical composition of claim 1 , wherein said nucleotide sequence encodes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, AND SEQ ID NO: 12, or a catalytically active fragment of any of the foregoing.
4 . The pharmaceutical composition of claim 1 , wherein the nucleotide sequence comprises at least one sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, or a catalytically active fragment of any of the foregoing.
5 . A pharmaceutical composition comprising a 2′-5′ oligoadenylate synthetase, or at least one catalytically active fragment thereof, and a pharmaceutically acceptable carrier.
6 . The pharmaceutical composition of claim 5 , wherein the composition comprises a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, and SEQ ID NO:12, or a catalytically active fragment of the foregoing.
7 . A vector comprising a nucleotide sequence encoding a 2′-5′ oligoadenylate synthetase, or at least one catalytically active fragment thereof; and a promoter sequence operably linked to said nucleotide sequence.
8 . The vector of claim 7 , wherein said nucleotide sequence encodes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, AND SEQ ID NO: 12, or a catalytically active fragment of any of the foregoing.
9 . The vector of claim 7 , wherein said nucleotide sequence comprises at least one sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, or a catalytically active fragment of any of the foregoing.
10 . The vector of claim 7 , wherein said vector is a viral vector.
11 . The vector of claim 10 , wherein said viral vector is an adenoviral vector or adeno-associated viral vector.
12 . A host cell that has been genetically modified with a nucleotide sequence encoding a 2′-5′ oligoadenylate synthetase, or at least one catalytically active fragment thereof, wherein said nucleotide sequence is expressed in said cell.
13 . The host cell of claim 12 , wherein said nucleotide sequence encodes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, AND SEQ ID NO: 12, or a catalytically active fragment of any of the foregoing.
14 . The host cell of claim 12 , wherein said nucleotide sequence comprises at least one sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, or a catalytically active fragment of any of the foregoing.
15 . The host cell of claim 12 , wherein said host cell is a prokaryotic cell.
16 . The host cell of claim 12 , wherein said host cell is a eukaryotic cell.
17 . The host cell of claim 12 , wherein said host cell is a mammalian cell.
18 . The host cell of claim 12 , wherein said host cell is a human cell.