Modulation of growth hormone receptor expression and insulin-like growth factor expression
View Patent ↗Compounds, compositions and methods are provided for modulating the expression of growth hormone receptor and/or insulin like growth factor-I (IGF-I). The compositions comprise oligonucleotides, targeted to nucleic acid encoding growth hormone receptor. Methods of using these compounds for modulation of growth hormone receptor expression and for diagnosis and treatment of disease associated with expression of growth hormone receptor and/or insulin-like growth factor-I are provided. Diagnostic methods and kits are also provided.
1. A modified oligonucleotide 20 nucleobases in length targeted to a nucleic acid molecule encoding growth hormone receptor, wherein said modified oligonucleotide consists of a nucleobase sequence recited in SEQ ID NO: 22, 23, 24, 25, 28, 29, 30, 31, 32, 34, 35, 37, 40, 44, 45, 48, 51, 52, 54, 55, 56, 57, 58, 60, 61, 62, 63, 64, 66, 67, 68, 69, 71, 73, 74, 75, 76, 79, 81, 82, 84, 85, 87, 88, 89, 91, 92, or 94; wherein said modified oligonucleotide consists of a ten deoxynucleotide region flanked on both the 5′ and 3′ end of said ten deoxynucleotide region with five 2′-O-(2-methoxyethyl) nucleotides, wherein each internucleoside linkage in said modified oligonucleotide is a phosphorothioate linkage and each cytosine in said modified oligonucleotide is a 5-methylcytosine; and wherein said modified oligonucleotide inhibits the expression of growth hormone receptor.
2. A method of inhibiting the expression of growth hormone receptor in cells or tissues comprising contacting said cells or tissues with the modified oligonucleotide of claim 1 .
3. A kit or assay device comprising the modified oligonucleotide claim 1 .
4. A method of treating an animal having a disease or condition associated with growth hormone receptor signalling or the growth hormone/insulin-like growth factor axis comprising administering to said animal a therapeutically or prophylactically effective amount of the modified oligonucleotide of claim 1 .
5. A method according to claim 4 in which the animal is a human.
6. A method of inhibiting the expression of insulin-like growth factor-1 in cells or tissues comprising contacting said cells or tissues with the modified oligonucleotide of claim 1 so that expression of growth hormone receptor and insulin-like growth factor-1 are inhibited.
7. A method of decreasing the number of blood vessels in the retina of an animal with retinopathy comprising administering to said animal an effective amount of the modified oligonucleotide of claim 1 .
8. The method of claim 7 wherein the retinopathy is retinopathy of prematurity.
9. The method of claim 7 wherein the animal is a mouse or a human.
10. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.