Methods for inhibiting expression of connective tissue growth factor
View Patent ↗This invention provides compounds which comprise modified oligonucleotides capable of inhibitory expression of connective tissue factor and composition containing same as well as methods of treating hyperprolific disorders and fibrotic diseases, and of reducing scarring resulting from wound healing using such compounds.
1. A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising a compound which comprises a modified oligonucleotide consisting of 12-30 linked nucleosides, at least a 12 nucleobase sequence portion of which is present within the nucleobase sequence set forth in SEQ ID NO: 39, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of linked deoxynucleosides;
(b) a 5′ wing segment consisting of linked modified nucleosides; and
(c) a 3′ wing segment consisting of linked modified nucleosides;
wherein the gap segment is positioned between the 5 wing segment and the 3′ wing segment, and wherein each modified nucleoside within each wing segment comprises a modified sugar.
2. The method of claim 1 , wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of thirteen linked deoxynucleosides;
(b) a 5′ wing segment consisting of two linked modified nucleosides; and
(c) a 3′ wing segment consisting of five linked modified nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each modified nucleoside within each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphothioate linkage.
3. The method of claim 1 , wherein in the modified oligonucleotide at least one internucleoside linkage is modified.
4. The method of claim 3 , wherein each modified internucleoside linkage is a phosphorothioate linkage.
5. The method of claim 3 , wherein each of the remaining internucleoside linkages is a phosphodiester linkage.
6. The method of claim 4 , wherein each of the internucleoside linkages is a phosphorothioate linkage.
7. The method of claim 1 , wherein in the modified oligonucleotide the modified sugar is a 2′-O-methoxyethyl sugar.
8. The method of claim 1 , wherein in the modified oligonucleotide at least one nucleobase is modified.
9. The method of claim 1 , wherein in the modified oligonucleotide at least one cytosine nucleobase is modified.
10. The method of claim 9 , wherein each modified cytosine nucleobase is a 5′-methylcytosine.
11. The method of claim 10 , wherein each cytosine within the nucleobase sequence of said modified oligonucleotide is a 5′-methylcytosine.
12. The method of claim 1 , wherein said composition is administered topically.
13. The method of claim 1 , wherein said composition is administered subcutaneously.
14. The method of claim 1 , wherein said composition is administered intradermally.
15. The method of claim 1 , wherein said composition is administered locally into fibrotic tissue.
16. The method of claim 1 , wherein the hypertrophic scarring results from dermal wound healing.
17. The method of claim 16 , wherein the wound is selected from the group consisting of skin breakage, surgical incision and burn.
18. The method of claim 1 , wherein after treatment said subject experiences an improvement in scar severity at least by an amount selected from the group consisting of 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 99%.
19. A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising a compound which comprises a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence as recited in SEQ ID NO 39, wherein the modified oligonucleotide comprises:
(a) a gap segment consisting of thirteen linked deoxynucleosides;
(b) a 5′ wing segment consisting of two linked modified nucleosides; and
(c) a 3′ wing segment consisting of five linked modified nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment,
wherein each modified nucleoside within each wing segment comprises a 2′-O-methoxyethyl sugar,
wherein each internucleoside linkage is a phosphorothioate linkage, and
wherein each cytosine nucleobase is a 5′-methylcytosine.
20. A method of treating hypertrophic scarring, comprising administering to a subject in need of treatment for hypertrophic scarring a therapeutically effective amount of a composition comprising an antisense oligonucleotide consisting of the nucleotide sequence of SEQ ID NO:39, said antisense oligonucleotide further characterized as having, from 5′ to 3′ direction,
a 5′ wing segment consisting of two nucleotides, a gap segment consisting of 13 nucleotides, and a 3′ wing segment consisting of five nucleotides,
wherein each nucleotide of said 5′ and 3′ wing segments comprises a 2′-O-methoxyethyl sugar,
wherein each nucleotide of said gap segment comprises a deoxyribose sugar,
wherein each cytosine base of said antisense oligonucleotide is a 5′-methylcytosine, and
wherein the internucleotide linkages between each nucleotide of said antisense oligonucleotide are phosphorothioate linkages.
21. The method of claim 20 , wherein said composition is administered topically.
22. The method of claim 20 , wherein said composition is administered subcutaneously.
23. The method of claim 20 , wherein said composition is administered intradermally.
24. The method of claim 20 , wherein said composition is administered locally into fibrotic tissue.
25. The method of claim 20 , wherein the hypertrophic scarring results from dermal wound healing.
26. The method of claim 25 , wherein the wound is selected from the group consisting of skin breakage, surgical incision and burn.
27. The method of claim 20 , wherein after treatment said subject experiences an improvement in scar severity at least by an amount selected from the group consisting of 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 99%.