Therapeutic uses of inhibitors of RTP801
View Patent ↗The present invention provides novel molecules, compositions, methods and uses for treating microvascular disorders, eye diseases respiratory conditions and hearing disorders based upon inhibition of the RTP801 gene and/or protein.
1. A double-stranded compound having the structure:
5′ (N) x -Z 3′
(antisense strand)
3′ Z′-(N′) y 5′
(sense strand)
wherein each N and N′ is a ribonucleotide which may be modified or unmodified in its sugar residue and each of (N) x and (N′) y is an oligomer in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;
wherein each of x and y is an integer between 19 and 40 inclusive;
wherein each of Z and Z′ may be present or absent, but if present is dTdT and is covalently attached at the 3′ terminus of the strand in which it is present; and
wherein the sequence of (N) x comprises a sequence set forth in either of SEQ ID NOs: 525 or 528.
2. A compound having the structure:
wherein each of A, C, G and U independently represents an unmodified or modified ribonucleotide; and
wherein each vertical line represents base pairing.
3. A compound according to claim 2 , wherein a sugar residue in at least one ribonucleotide is modified.
4. A compound according to claim 3 , wherein the sugar residue is modified by replacing a 2′ OH with —H, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —NH 2 , or —F.
5. A compound according to claim 4 , wherein the sugar residue is modified with a 2′-OCH 3 .
6. A compound according to claim 5 wherein x=y=19.
7. A compound according to claim 6 , wherein alternating ribonucleotides in each of the antisense strand and the sense strand comprise a 2′-OCH 3 sugar modification;
wherein the ribonucleotide at each of the 5′ terminus and the 3′ terminus of the antisense strand comprises a 2′-OCH 3 sugar modification;
wherein the ribonucleotide at each of the 5′ terminus and the 3′ terminus of the sense strand is unmodified; and
wherein the ribonucleotide at the 5′ terminus and the 3′ terminus of the antisense strand and the sense strand is independently phosphorylated or non-phosphorylated.
8. A compound according to claim 7 , wherein the antisense strand and the sense strand are non-phosphorylated.
9. A compound according to claim 7 , wherein the antisense strand and the sense strand are phosphorylated.
10. A compound according to claim 1 , wherein a dTdT is covalently attached at the 3′ terminus of the antisense strand and of the sense strand.
11. A compound having the structure:
wherein each of A, C, G and U independently represents an unmodified or modified ribonucleotide; and
wherein each vertical line represents base pairing.
12. A compound according to claim 1 , wherein a sugar residue in at least one ribonucleotide is modified.
13. A compound according to claim 12 , wherein the sugar residue is modified by replacing a 2′ OH with —H, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —NH 3 , or —F.
14. A compound according to claim 13 , wherein the sugar residue is modified with a 2′-OCH 3 .
15. A compound according to claim 14 wherein x=y=19.
16. A compound according to claim 15 , wherein alternating ribonucleotides in each of the antisense strand and the sense strand comprise a 2′-OCH 3 sugar modification;
wherein the ribonucleotide at each of the 5′ terminus and the 3′ terminus of the antisense strand comprises a 2′-OCH 3 sugar modification;
wherein the ribonucleotide at each of the 5′ terminus and the 3′ terminus of the sense strand is unmodified; and
wherein the ribonucleotide at the 5′ terminus and the 3′ terminus of the antisense strand and the sense strand is independently phosphorylated or non-phosphorylated.
17. A compound according to claim 16 , wherein the antisense strand and the sense strand are non-phosphorylated.
18. A compound according to claim 16 , wherein the antisense strand and the sense strand are phosphorylated.
19. A composition comprising a compound of claim 2 , and a pharmaceutically acceptable carrier.
20. A composition comprising a compound of claim 7 , and a pharmaceutically acceptable carrier.
21. A composition comprising a compound of claim 11 , and a pharmaceutically acceptable carrier.
22. A composition comprising a compound of claim 16 , and a pharmaceutically acceptable carrier.