US2003032609A1PendingUtilityA1
Methods of modulating of angiogenesis
Priority: Aug 14, 1998Filed: Apr 12, 2002Published: Feb 13, 2003
Est. expiryAug 14, 2018(expired)· nominal 20-yr term from priority
A61K 38/00G06F 16/289C07K 14/47
52
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Claims
Abstract
A method of inhibiting angiogenesis in a mammal by administering to the mammal a compound which inhibits binding of endothelial PAS domain protein-1 to cis-acting transcription regulatory sequence in the promoter region of a gene encoding an angiogenic factor.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of inhibiting angiogenesis in a mammal comprising administering to said mammal a compound which inhibits binding of endothelial PAS domain protein-1 (EPAS1) to cis-acting transcription regulatory DNA of an angiogenic factor.
2 . The method of claim 1 , wherein said angiogenic factor is a vascular endothelial growth factor receptor (VEGF-R).
3 . The method of claim 2 , wherein said receptor is KDR/flk-1.
4 . The method of claim 2 , wherein said receptor is flt-1.
5 . The method of claim 1 , wherein said angiogenic factor is vascular endothelial growth factor (VEGF).
6 . The method of claim 1 , wherein said angiogenic factor is Tie2.
7 . The method of claim 1 , wherein said compound inhibits transcription of said angiogenic factor.
8 . The method of claim 1 , wherein said regulatory DNA comprises GCCCTACGTGCTGTCTCA (SEQ ID NO: 1 ).
9 . The method of claim 1 , wherein said compound is an EPAS1 polypeptide lacking a transactivation domain.
10 . The method of claim 9 , wherein said transactivation domain comprises the amino acid sequence of SEQ ID NO: 2 .
11 . The method of claim 9 , wherein said transactivation domain comprises the amino acids 486 - 639 of SEQ ID NO: 6 .
12 . The method of claim 9 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 4 .
13 . The method of claim 1 , wherein said compound is a nucleic acid encoding an EPAS1 polypeptide lacking the amino acid sequence of SEQ ID NO: 2 .
14 . The method of claim 1 , wherein said compound is a nucleic acid encoding an EPAS1 polypeptide lacking amino acids 486 - 639 of SEQ ID NO: 6 .
15 . The method of claim 1 , wherein said compound is a antisense nucleic acid molecule comprising at least 10 nucleotides, wherein the sequence of said molecule is complementary to part of or all ofan MRNA encoding EPAS1 polypeptide.
16 . The method of claim 1 , wherein said compound is an EPAS1-specific intrabody.
17 . The method of claim 1 , wherein said compound is administered to a site of an atherosclerotic lesion in said mammal.
18 . The method of claim 1 , wherein said compound is administered to a tumor site in said mammal.
19 . An antibody which binds to EPAS1 .
20 . The antibody of claim 19 , wherein said antibody binds to a C-terminal activation domain of EPAS1.
21 . The antibody of claim 20 , wherein said activation domain comprises SEQ ID NO: 2 .
22 . A method of promoting angiogenesis in a mammal comprising administering to said mammal a compound which increases expression of VEGF or a VEGF-R in an endothelial cell.
23 . The method of claim 19 , wherein said VEGF-R is KDR/flk-1 or flt-1.
24 . A substantially pure DNA comprising a sequence encoding a aryl hydrocarbon receptor nuclear translocator-4 (ARNT4) polypeptide.
25 . The DNA of claim 24 , wherein said DNA encodes a human ARNT4 polypeptide.
26 . The DNA of claim 24 , wherein said polypeptide comprises the amino acid sequence of residues 75 to 128 , inclusive, of SEQ ID NO: 19 .
27 . The DNA of claim 24 , wherein said polypeptide comprises the amino acid sequence of residues 155 to 207 , inclusive, of SEQ ID NO: 19 .
28 . The DNA of claim 24 , wherein said polypeptide comprises the amino acid sequence of residues 232 to 384 , inclusive, of SEQ ID NO: 19 .
29 . A substantially pure DNA comprising a nucleotide sequence having at least 50% sequence identity to SEQ ID NO: 20 .
30 . The DNA of claim 24 , wherein said DNA comprises the coding sequences of SEQ ID NO: 20 .
31 . The DNA of claim 24 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 19 .
32 . A substantially pure DNA comprising a strand which hybridizes at high stringency to a strand of DNA consisting of the coding sequence of SEQ ID NO: 20 , or the complement thereof.
33 . A substantially pure DNA comprising a sequences at least 50% sequence identity to the coding sequence of SEQ ID NO: 20 , and encoding a polypeptide having the biological activity of an ARNT4 polypeptide.
34 . A substantially pure ARNT4 polypeptide.
35 . The polypeptide of claim 34 , wherein said polypeptide is human ARNT4.
36 . The polypeptide of claim 34 , wherein said polypeptide comprises the amino acid sequence of residues 75 to 128 , inclusive, of SEQ ID NO: 19 .
37 . The polypeptide of claim 34 , wherein said polypeptide comprises the amino acid sequence of residues 155 to 207 , inclusive, of SEQ ID NO: 19 .
38 . The polypeptide of claim 34 , wherein said polypeptide comprises the amino acid sequence of residues 232 to 384 , inclusive, of SEQ ID NO: 19 .
39 . The polypeptide of claim 34 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 19 .
40 . The polypeptide of claim 34 , wherein said polypeptide comprises an amino acid sequence at least 50% identical to SEQ ID NO: 19 .
41 . The polypeptide of claim 34 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 19 .
42 . A vector comprising the DNA of claim 24 .
43 . A host cell comprising the DNA of claim 24 .
44 . A transgenic non-human animal the germ cells and nucleated somatic cells of which comprise a null mutation in a gene encoding ARNT4.
45 . A method of inhibiting angiogenesis in a mammal comprising administering to said mammal a compound which inhibits binding of EPAS1 to ARNT4.
46 . The method of claim 45 , wherein said compound is an ARNT4 polypeptide.
47 . The method of claim 45 , wherein said polypeptide comprises the amino acid sequence of residues 75 to 128 , inclusive, of SEQ ID NO: 19 .
48 . The method of claim 45 , wherein said polypeptide comprises the amino acid sequence of residues 155 to 207 , inclusive, of SEQ ID NO: 19 .
49 . The method of claim 45 , wherein said polypeptide comprises the amino acid sequence of residues 232 to 384 , inclusive, of SEQ ID NO: 19 .
50 . The method of claim 45 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 19 .
51 . An EPAS1 polypeptide lacking a transactivation domain.
52 . The polypeptide of claim 51 , wherein said transactivation domain comprises the amino acid sequence of SEQ ID NO: 2 .
53 . The polypeptide of claim 51 , wherein said transactivation domain comprises the amino acids 486 - 639 of SEQ ID NO: 6 .
54 . The polypeptide of claim 51 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 4 .
55 . A nucleic acid encoding an EPAS1 polypeptide lacking the amino acid sequence of SEQ ID NO: 2 .
56 . The nucleic acid of claim 55 , wherein said nucleic acid encodes an EPASI polypeptide lacking amino acids 486 - 639 of SEQ ID NO: 6 .Join the waitlist — get patent alerts
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