Materials and Methods for the Treatment of Hypertension
The present invention is directed to materials and methods for the treatment of hypertension and ischemia comprising administering at least one therapeutic agent selected from the group consisting of vascular endothelial growth factor-C product and vascular endothelial growth factor-D product, and optionally, when treating hypertension, a standard of care anti-hypertensive agent.
1 . A method of treating a mammalian subject suffering from hypertension, comprising:
administering to said subject a composition comprising at least one therapeutic agent selected from the group consisting of a VEGF-C growth factor product and a VEGF-D growth factor product, wherein said composition is administered in an amount effective to reduce systolic or diastolic blood pressure in said subject.
2 - 4 . (canceled)
5 . The method according to claim 1 , wherein said mammalian subject is human.
6 . The method according to claim 5 , wherein the at least one therapeutic agent comprises a VEGF-C growth factor product that comprises a VEGF-C polypeptide.
7 . The method according to claim 6 , wherein the VEGF-C polypeptide comprises a member selected from the group consisting of a full length VEGF-C polypeptide, a VEGF-CΔNΔC polypeptide, a VEGF-CΔN polypeptide, and a VEGF-CΔC polypeptide.
8 . (canceled)
9 . The method according to claim 6 , wherein the VEGF-C polypeptide is selected from the group consisting of a polypeptide selected from the group consisting of:
(a) a polypeptide comprising amino acids 1-419 of SEQ ID NO: 2 or a polypeptide comprising amino acids 32-419 of SEQ ID NO: 2;
(b) a polypeptide comprising amino acids 103-227 of SEQ ID NO: 2;
(c) N-terminal deletion fragments of (a) or (b) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3;
(d) C-terminal deletion fragments of (a) or (b) or (c) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3 ;
(e) polypeptides that comprise an amino acid sequence at least 90% identical to (a) or (b) or (c) or (d) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3; and
(f) polypeptides according to (a), (b), (c), (d), or (e), wherein the cysteine corresponding to position 156 of SEQ ED NO: 2 has been deleted or replaced with another amino acid and wherein the polypeptides bind and stimulate phosphorylation of VEGFR-3.
10 . (canceled)
11 . The method according to claim 5 , wherein the at least one therapeutic agent comprises a VEGF-D growth factor product that comprises a VEGF-D polypeptide.
12 . The method according to claim 11 , wherein the VEGF-D polypeptide is selected from the group consisting of a full length VEGF-D polypeptide, a VEGF-DΔNΔC polypeptide, a VEGF-DΔN polypeptide, and a VEGF-DΔC polypeptide.
13 . (canceled)
14 . The method according to claim 11 , wherein the VEGF-D polypeptide is selected from the group consisting of:
(a) a polypeptide comprising amino acids 1-354 of SEQ ID NO: 4 or a polypeptide comprising amino acids 22-354 of SEQ ID NO: 4;
(b) a polypeptide comprising amino acids 93-201 of SEQ ID NO: 4;
(c) N-terminal deletion fragments of (a) or (b) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3;
(d) C-terminal deletion fragments of (a) or (b) or (c) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3; and
(e) polypeptides that comprise an amino acid sequence at least 90% identical to (a) or (b) or (c) or (d) that bind and stimulate phosphorylation of VEGFR-2 and/or VEGFR-3.
15 . The method according to claim 5 , wherein the at least one therapeutic agent comprises a VEGF-C growth factor product that is a polynucleotide comprising a nucleotide sequence that encodes a VEGF-C polypeptide.
16 . The method according to claim 5 , wherein the at least one therapeutic agent comprises a VEGF-D growth factor product that is a polynucleotide comprising a nucleotide sequence that encodes a VEGF-D polypeptide.
17 . The method according to claim 15 , wherein the composition comprises a vector comprising the polynucleotide operatively connected to at least one expression control sequence.
18 . The method according to claim 17 , wherein the vector comprises a replication-deficient viral vector.
19 . The method according to claim 18 , wherein the vector comprises a member selected from the group consisting of adenoviral vectors, adeno-associated virus vectors, lentivirus vectors, herpes virus vectors, and vaccinia virus vectors.
20 . The method according to claim 5 , wherein the subject suffers from hypertension and the method further comprises administering at least one standard of care anti-hypertensive agent to the subject.
21 . The method according to claim 20 , wherein the standard of care anti-hypertensive agent is selected from the group consisting of Coenzyme Q10, renin inhibitors, angiotensin-convertin enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), alpha blockers, diuretics, beta blockers and calcium channel blockers.
22 - 36 . (canceled)
37 . The method according to claim 5 , wherein the method further comprises administering a VEGF growth factor product to the subject.
38 . The method according to claim 5 , wherein the composition further comprises a pharmaceutically-acceptable carrier, excipient or diluent.
39 - 44 . (canceled)
45 . A method of treating hypertension in a subject, the method comprising
(a) identifying a subject as being resistant to treatment with a standard of care anti-hypertensive agent; and
(b) administering to said subject a composition comprising at least one therapeutic agent selected from the group consisting of a VEGF-C growth factor product and a VEGF-D growth factor product, wherein said composition is administered in an amount effective to reduce systolic or diastolic blood pressure in said subject.
46 . The method according to claim 45 , wherein the identifying comprises measuring the blood pressure of a subject before and after combination therapy with at least three anti-hypertensive agents, wherein at least one of the anti-hypertensive agents is a diuretic, and
wherein the continued elevation of blood pressure of the subject after the combination therapy identifies the subject as being resistant to treatment with a standard of care anti-hypertensive agent.
47 - 52 . (canceled)
53 . A composition that comprises a VEGF-D therapeutic or a VEGF-C therapeutic in admixture with a standard of care anti-hypertensive therapeutic.
54 - 59 . (canceled)