Methods for Inhibiting Angiogenesis and/or Lymphangiogenesis
Proprotein convertase inhibitor has been found to block proteolytic processing and activation of VEGF-C and VEGF-D and inhibit angiogenesis and/or lymphangiogenesis. Method and composition are disclosed for inhibiting angiogenesis and/or lymphangiogenesis, and for treating conditions associated with excessive angiogenesis, such as tumors and/or retinopathies, as well as conditions associated with lymphangiogenesis, such as the metastatic spread of malignancies, macular degeneration, inflammatory mediated diseases, rheumatoid arthritis, diabetic retinopathy and psoriasis in a patient. The inventive method and composition utilize proprotein convertase antagonist selected from the group consisting of an anti-proprotein convertase antibody, an antisense nucleic acid molecule against a polynucleotide coding for a proprotein convertase, and an siRNA for inhibiting proprotein convertase expression, as well as proprotein convertase inhibitors.
1 . A method of inhibiting angiogenesis or lymphangiogenesis comprising administering to an organism in need of inhibition of angiogenesis or lymphangiogenesis a composition that comprises a proprotein convertase inhibitor effective to inhibit angiogenesis or lymphangiogenesis.
2 . The method of claim 1 , wherein the proprotein convertase inhibitor is an inhibitor specific for furin.
3 . The method of claim 2 , wherein the inhibitor comprises a member selected from the group consisting of:
(a) antibody substances that bind to a proprotein convertase polypeptide and that inhibit proprotein convertase function; and
(b) inhibitory nucleic acids.
4 . The method of claim 3 , wherein the inhibitor comprises an antibody substance selected from the group consisting of: (a) a monoclonal antibody; (b) antigen binding fragments of proprotein convertase antibodies; and (c) domain antibodies (dAbs).
5 . The method of claim 3 , wherein the inhibitor comprises an antibody fragment selected from the group consisting of Fab fragments, F(ab)2 fragments, Fab′ fragments, F(ab′)2 fragments, Fd fragments, Fd′ fragments, Fv fragments, and single chain antibodies.
6 . The method of claim 3 , wherein the inhibitor comprises a human or humanized antibody substance.
7 . The method of claim 3 , wherein the inhibitor is an inhibitory nucleic acid selected from the group consisting of: (a) an antisense oligonucleotide; (b) an inhibitory RNA; (c) a DNA enzyme; (d) a ribozyme; (e) an aptamer.
8 . The method of claim 7 , wherein the inhibitor is an inhibitory RNA.
9 . She method of claim 7 , wherein the inhibitory RNA is a short interfering RNA, a double stranded RNA (dsRNA).
10 . The method of claim 7 , wherein the inhibitory RNA is a short hairpin RNA (shRNA).
11 . The method of claim 10 , wherein the shRNA comprises at least one sequence selected from the group consisting of SEQ ID Nos: 15, 16, 17 and 18.
12 . The method of claim 11 , wherein the inhibitor is an inhibitory RNA that targets a portion of the furin cDNA sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 20.
13 . The method of claim 3 , wherein the composition comprises an expression vector that contains an insert that comprises a nucleotide sequence that encodes the inhibitor.
14 . The method of claim 2 , wherein the composition further comprises a pharmaceutically acceptable carrier.
15 . A method according to claim 2 , wherein said organism is a mammal.
16 . A method according to claim 2 , wherein said organism is human.
17 . A method according to claim 2 , wherein said organism has a tumor.
18 . A method according to claim 2 , wherein said organism has macular degeneration.
19 . A method for inhibiting angiogenesis or lymphangiogenesis in an organism, comprising:
contacting the organism with a double stranded siRNA molecule under conditions suitable to modulate the expression of a proprotein convertase gene in the organism via RNA interference, wherein a first strand of the double stranded siNA molecule comprises nucleotide sequence having sufficient complementarity to proprotein convertase mRNA, and wherein a second strand of the double stranded siRNA molecule comprises nucleotide sequence having sufficient complementarity to the first strand, for the siRNA molecule to inhibit expression of the proprotein convertase gene via RNA interference.