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 selected from the group consisting of SEQ ID NO:88, SEQ ID NO:203 and SEQ ID NO:262.
2. The oligonucleotide of claim 1 , wherein the modification of the oligonucleotide comprises the incorporation of at least one non-naturally occurring internucleoside linkage, sugar moiety, or nucleobase.
3. The oligonucleotide of claim 2 , wherein the at least one non-naturally occurring internucleoside linkage is a phosphothioate internucleoside linkage.
4. The oligonucleotide of claim 2 , wherein all of the internucleoside linkages are phosphothioate internucleoside linkages.
5. The oligonucleotide of claim 2 , wherein the at least one non-naturally occurring sugar moiety is a bicyclic sugar.
6. The oligonucleotide of claim 2 , wherein the at least one non-naturally occurring sugar comprises a 2′-O,4′-C-methylene bridge.
7. The oligonucleotide of claim 2 , wherein the at least one non-naturally occurring nucleobase is a 5-methylcytosine.
8. A method of treating a connective tissue growth factor (CTGF)-associated disorder comprising, administering to a subject in need thereof, an effective amount of a modified antisense oligonucleotide selected from the group consisting of SEQ ID NO:88, SEQ ID NO:203 and SEQ ID NO:262, thereby treating the CTGF-associated disorder.
9. The method of claim 8 , 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.
10. The method of claim 9 , 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.