Methods and compositions for treating inflammatory conditions
The present invention is directed to methods of treating an inflammatory condition in a patient. This method includes providing a therapeutic agent that is a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist or a nucleic acid molecule encoding a VEGFR-3 agonist. The present invention is further directed to pharmaceutical compositions and therapeutic systems for treating an inflammatory condition.
1. A method of treating an inflammatory joint condition in a patient comprising:
providing a therapeutic agent comprising a nucleic acid molecule encoding a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist selected from the group consisting of VEGF-C protein or active fragment thereof, VEGF-C C152S mutant protein or active peptide fragment thereof, and VEGF-C C156S mutant protein or active peptide fragment thereof, wherein said nucleic acid molecule is operably linked to a promoter sequence that initiates expression of the VEGFR-3 agonist in an affected joint; and
administering the therapeutic agent directly to the affected joint of the patient having the inflammatory joint condition under conditions effective to initiate expression of the VEGFR-3 agonist in the joint, wherein said administering is effective to treat the inflammatory joint condition.
2. The method according to claim 1 , wherein the inflammatory joint condition is a condition occurring around a joint.
3. The method according to claim 1 , wherein the nucleic acid molecule is present in an expression vector.
4. The method according to claim 1 wherein the therapeutic agent is administered to the patient in combination with an agent that inhibits VEGF/VEGFR-1 or VEGF/VEGFR-2 signaling.
5. The method according to claim 4 , wherein the agent is selected from the group consisting of a VEGFR-1 or VEGFR-2 antibody or aptamer; a VEGFR-1 or VEGFR-2 inhibitory peptide or polypeptide fragment; a polypeptide comprising a soluble VEGFR-1 or VEGFR-2 or fragment thereof; and a VEGF, VEGFR-1, or VEGFR-2 antisense polynucleotide or siRNA.
6. The method according to claim 1 wherein the therapeutic agent is administered to the patient in combination with an anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor, a TNFα inhibitor, a biologic response modifiers, and combinations thereof.
7. The method according to claim 1 , wherein said administering is carried out intrasynovially or intra-articularly.
8. A method of treating a patient having an arthritic joint condition, the method comprising:
providing a therapeutic agent comprising a nucleic acid molecule encoding a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist selected from the group consisting of VEGF-C protein or active fragment thereof, VEGF-C C152S mutant protein or active peptide fragment thereof, and VEGF-C C156S mutant protein or active peptide fragment thereof, wherein said nucleic acid molecule is operably linked to a promoter sequence that initiates expression of the VEGFR-3 agonist in an arthritic joint; and
administering the therapeutic agent directly to the arthritic joint of the patient having the arthritic condition under conditions effective to initiate expression of the VEGFR-3 agonist, wherein said administering is effective to treat the arthritic joint condition.
9. The method according to claim 8 , wherein the arthritic condition is rheumatoid arthritis.
10. The method according to claim 8 , wherein the arthritic condition is psoriatic arthritis.
11. The method according to claim 8 , wherein the arthritic condition is inflammatory arthritis.
12. The method according to claim 8 , wherein the arthritic condition is ankylosing spondylitis.
13. The method according to claim 8 , wherein the nucleic acid molecule is present in an expression vector.
14. The method according to claim 8 , wherein the therapeutic agent is administered to the patient in combination with an agent that inhibits VEGF/VEGFR-1 or VEGF/VEGFR-2 signaling.
15. The method according to claim 14 , wherein the agent is selected from the group consisting of a VEGFR-1 or VEGFR-2 antibody or aptamer; a VEGFR-1 or VEGFR-2 inhibitory peptide or polypeptide fragment; a polypeptide comprising a soluble VEGFR-1 or VEGFR-2 or fragment thereof; and a VEGF, VEGFR-1, or VEGFR-2 antisense polynucleotide or siRNA.
16. The method according to claim 8 , wherein the therapeutic agent is administered to the patient in combination with an anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor, a TNFα inhibitor, a biologic response modifiers, and combinations thereof.
17. The method according to claim 8 , where said administering is effective to maintain joint function, reduce synovitis, inhibit bone destruction, and/or inhibit cartilage destruction.
18. The method according to claim 8 , wherein the arthritic condition is osteoarthritis.
19. The method according to claim 1 , wherein the inflammatory joint condition is a condition occurring in a joint.
20. A method of treating an inflammatory joint condition in a patient comprising:
providing a therapeutic agent comprising an adenoviral vector, adeno-associated viral vector, retroviral vector, or plasmid vector, wherein said vector comprises a nucleic acid sequence encoding a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist selected from the group consisting of VEGF-C protein or active fragment thereof, VEGF-C C152S mutant protein or active peptide fragment thereof, and VEGF-C C156S mutant protein or active peptide fragment thereof, wherein said nucleic acid sequence is operably linked to a promoter sequence that initiates expression of the VEGFR-3 agonist in an affected joint; and
administering the therapeutic agent directly to the affected joint of the patient having the inflammatory joint condition under conditions effective to initiate expression of the VEGFR-3 agonist, wherein said administering is effective to treat the inflammatory joint condition.
21. The method according to claim 20 , wherein the inflammatory joint condition is a condition occurring around a joint.
22. The method according to claim 20 , wherein the inflammatory joint condition is a condition occurring in a joint.
23. The method according to claim 20 , wherein the therapeutic agent is administered to the patient in combination with an agent that inhibits VEGF/VEGFR-1 or VEGF/VEGFR-2 signaling.
24. The method according to claim 20 , wherein the agent is selected from the group consisting of a VEGFR-1 or VEGFR-2 antibody or aptamer; a VEGFR-1 or VEGFR-2 inhibitory peptide or polypeptide fragment; a polypeptide comprising a soluble VEGFR-1 or VEGFR-2 or fragment thereof; and a VEGF, VEGFR-1, or VEGFR-2 antisense polynucleotide or siRNA.
25. The method according to claim 20 wherein the therapeutic agent is administered to the patient in combination with an anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor, a TNFα inhibitor, a biologic response modifiers, and combinations thereof.
26. The method according to claim 20 , wherein said administering is carried out intrasynovially or intra-articularly.