Connective tissue growth factor antisense oligonucleotides
The present invention relates to antisense oligonucleotides that target human CTGF mRNA and inhibit CTGF mRNA expression. Additionally, regions of human CTGF mRNA that are exceptionally sensitive to antisense inhibition are disclosed. Pharmaceutical compositions comprising the antisense oligonucleotides are further disclosed. These compositions are useful for treating disorders and conditions that are associated with or influenced by CTGF expression.
1. A modified antisense oligonucleotide, 12 to 20 nucleotides in length, that is complementary to a region of human connective tissue growth factor (CTGF) mRNA and comprises at least 12 consecutive nucleotides of an oligonucleotide selected from the group consisting of SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 232, SEQ ID NO: 106, SEQ ID NO: 233 and SEQ ID NO: 276.
2. A modified antisense oligonucleotide between 12 and 30 nucleotides in length that is complementary to a region within nucleotides 1185 to 1216 of SEQ ID NO:1.
3. The oligonucleotide of claim 1 or 2 , wherein the modification of the oligonucleotide comprises the incorporation of at least one non-naturally occurring internucleoside linkage, sugar moiety, or nucleobase.
4. The oligonucleotide of claim 3 , wherein the at least one non-naturally occurring internucleoside linkage is a phosphothioate internucleoside linkage.
5. The oligonucleotide of claim 4 , wherein all of the internucleoside linkages are phosphothioate internucleoside linkages.
6. The oligonucleotide of claim 3 , wherein the at least one non-naturally occurring sugar moiety is a bicyclic sugar.
7. The oligonucleotide of claim 3 , wherein the at least one non-naturally occurring sugar comprises a 2′-O,4′-C-methylene bridge.
8. The oligonucleotide of claim 3 , wherein the at least one non-naturally occurring nucleobase is a 5-methylcytosine.
9. The modified antisense oligonucleotide of claim 1 that is complementary to a region of human connective tissue growth factor (CTGF) mRNA and comprises SEQ ID NO:274.
10. A modified antisense oligonucleotide selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 230, SEQ ID NO 231, SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 232, SEQ ID NO: 106, SEQ ID NO: 233 and SEQ ID NO: 276.
11. The modified antisense oligonucleotide of claim 2 , wherein the modified antisense oligonucleotide is between 12 and 20 nucleotides in length.
12. A method of treating a CTGF-associated disorder comprising, administering to a subject in need thereof, an effective amount of a modified antisense oligonucleotide, 12 to 30 nucleotides in length, that is complementary to a region within nucleotides 1185 to 1216 of SEQ ID NO: 1, thereby treating the CTGF-associated disorder.
13. The method of claim 12 , wherein the CTGF-associated disorder is selected from the group consisting of dermal fibrosis, liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, ocular fibrosis, scleroderma, surgical scars and adhesions, scars from wounds, scars from burns, restenosis, glomerular sclerosis, osteoarthritis and cancer.
14. The method of claim 13 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, dermatofibromas, breast cancer, breast carcinoma desmoplasia, angiolipoma, angioleiomyoma, desmoplastic cancer, prostate cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, and liver cancer.