Modified TGF-beta oligonucleotides
The invention refers to an oligonucleotide consisting of 10 to 20 nucleotides of selected regions of the TGF-beta1, TGF-beta2 or TGF-beta3 nucleic acid sequence, which comprises modified nucleotides such as LNA, ENA, polyalkylene oxide-, 2′-fluoro, 2′-O-methoxy and/or 2′-O-methyl modified nucleotides. The selected regions are preferably the region of nucleic acid no. 1380 to 1510, no. 1660 to 1680, no. 2390 to 2410, or no. 2740 to 2810 of the TGF-beta2 nucleic acid sequence of SEQ ID NO. 1, specific regions of the TGF-beta1 nucleic acid sequence of SEQ ID NO. 149, or specific regions of the TGF-beta3 nucleic acid sequence of SEQ ID No. 267. The invention further relates to pharmaceutical compositions comprising such oligonucleotide, wherein the composition or the oligonucleotide is used in the prevention and/or treatment of a malignant and/or benign tumor, an immunologic disease, fibrosis, glaucoma, etc.
1. A method of inhibiting and/or treating a malignant and/or benign tumor, fibrosis, cirrhosis, scleroderma or related dermatologic diseases, or a CNS disease, comprising:
administering an oligonucleotide to a subject in need thereof,
wherein said oligonucleotide is:
CAAAGTATTTGGTCTCC (SEQ. ID. NO. 47) wherein nucleotides in bold letters are LNA modified oligonucleotides, or
GACCAGATGCAGGA (SEQ ID NO. 2).
2. The method of claim 1 , wherein the method is directed to inhibiting and/or treating a malignant and/or benign tumor, and wherein the tumor is at least one of solid tumors, blood born tumors, leukemias, tumor metastasis, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, psoriasis, astrocytoma, acoustic neuroma, blastoma, Ewing's tumor, craniopharyngioma, ependymoma, medulloblastoma, glioma, hemangloblastoma, Hodgkins-lymphoma, medullablastoma, leukaemia, mesothelioma, neuroblastoma, neurofibroma, non-Hodgkins lymphoma, pinealoma, retinoblastoma, sarcoma, seminoma, trachomas, Wilm's tumor, bile duct carcinoma, bladder carcinoma, brain tumor, breast cancer, bronchogenic carcinoma, carcinoma of the kidney, cervical cancer, choriocarcinoma, choroidcarcinoma, cystadenocarcinome, embryonal carcinoma, epithelial carcinoma, esophageal cancer, cervical carcinoma, colon carcinoma, colorectal carcinoma, endometrial cancer, gallbladder cancer, gastric cancer, head cancer, liver carcinoma, lung carcinoma, medullary carcinoma, neck cancer, non- small-cell bronchogenic/lung carcinoma, ovarian cancer, pancreas carcinoma, papillary carcinoma, papillary adenocarcinoma, prostate cancer, small intestine carcinoma, prostate carcinoma, rectal cancer, renal cell carcinoma, retinoblastoma, skin cancer, small-cell bronchogenic/lung carcinoma, squamous cell carcinoma, sebaceous gland carcinoma, testicular carcinoma, and uterine cancer.
3. A method of inhibiting and/or treating a malignant and/or benign tumor, fibrosis, cirrhosis, scleroderma or related dermatologic diseases, or a CNS disease, comprising:
administering a pharmaceutical composition to a subject in need thereof, said pharmaceutical composition comprising:
an oligonucleotide and a pharmaceutically acceptable carrier;
wherein said oligonucleotide is:
CAAAGTATTTGGTCTCC (SEQ. ID. NO. 47) wherein nucleotides in bold letters are LNA modified oligonucleotides, or
GACCAGATGCAGGA (SEQ ID NO. 2).
4. The method of claim 3 , wherein the method is directed to inhibiting and/or treating a malignant and/or benign tumor, and wherein the tumor is at least one of solid tumors, blood born tumors, leukemias, tumor metastasis, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, psoriasis, astrocytoma, acoustic neuroma, blastoma, Ewing's tumor, craniopharyngioma, ependymoma, medulloblastoma, glioma, hemangloblastoma, Hodgkins-lymphoma, medullablastoma, leukaemia, mesothelioma, neuroblastoma, neurofibroma, non-Hodgkins lymphoma, pinealoma, retinoblastoma, sarcoma, seminoma, trachomas, Wilm's tumor, bile duct carcinoma, bladder carcinoma, brain tumor, breast cancer, bronchogenic carcinoma, carcinoma of the kidney, cervical cancer, choriocarcinoma, choroidcarcinoma, cystadenocarcinome, embryonal carcinoma, epithelial carcinoma, esophageal cancer, cervical carcinoma, colon carcinoma, colorectal carcinoma, endometrial cancer, gallbladder cancer, gastric cancer, head cancer, liver carcinoma, lung carcinoma, medullary carcinoma, neck cancer, non- small-cell bronchogenic/lung carcinoma, ovarian cancer, pancreas carcinoma, papillary carcinoma, papillary adenocarcinoma, prostate cancer, small intestine carcinoma, prostate carcinoma, rectal cancer, renal cell carcinoma, retinoblastoma, skin cancer, small-cell bronchogenic/lung carcinoma, squamous cell carcinoma, sebaceous gland carcinoma, testicular carcinoma, and uterine cancer.
5. The method of claim 1 , wherein the method is directed to treating a malignant and/or benign tumor, fibrosis, cirrhosis, scleroderma or related dermatologic diseases, or a CNS disease.
6. The method of claim 3 , wherein the method is directed to treating a malignant and/or benign tumor, fibrosis, cirrhosis, scleroderma or related dermatologic diseases, or a CNS disease.
7. The method of claim 1 , wherein the oligonucleotide is CAAAGTATTTGGTCTCC (SEQ. ID. NO. 47) and wherein nucleotides in bold letters are LNA modified oligonucleotides.
8. The method of claim 1 , wherein the oligonucleotide is GACCAGATGCAGGA (SEQ ID NO. 2).
9. The method of claim 3 , wherein the oligonucleotide is CAAAGTATTTGGTCTCC (SEQ. ID. NO. 47) and wherein nucleotides in bold letters are LNA modified oligonucleotides.
10. The method of claim 3 , wherein the oligonucleotide is GACCAGATGCAGGA (SEQ ID NO. 2).