Claims
- 1. A method of preventing or treating diabetic retinopathy comprising administering to a mammal a therapeutically effective amount of an inhibitor of retinal pericyte apoptosis.
- 2. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is an antioxidant compound.
- 3. The method according to claim 2, wherein the antioxidant compound is selected from the group consisting of N-acetyl-L-cysteine, lipoic acid, ebselen, zeaxanthin, coelenteramine, derivatives thereof and mixtures thereof.
- 4. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is an antioxidant compound which indirectly inhibits production of ceramides and/or DAG.
- 5. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is a compound that is an inhibitor of production of ceramides and/or DAG.
- 6. The method according to claim 5, wherein the compound that is an inhibitor of production of ceramides is an inhibitor of acid sphingomyelinase.
- 7. The method according to claim 6, wherein the inhibitor of acid sphingomyelinase is 10,11-dihydro-5-(3-(methylamino)propyl)-5H-dibenz(b,f)azepine (desipramine) or a derivative thereof.
- 8. The method according to claim 5, wherein the compound that is an inhibitor of the production of DAG is an inhibitor of phosphatidylcholine-phospholipase C.
- 9. The method according to claim 8, wherein the inhibitor of phosphatidylcholine-phospholipase C is tricyclo(5.21.0(2.6))decyl-(9)(8)xanthogenate (D609) or a derivative thereof.
- 10. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is a caspase inhibitor.
- 11. The method according to claim 10, wherein the caspase inhibitor is a peptide.
- 12. The method according to claim 11, wherein the caspase inhibitor is a peptide modified chemically by a benzyloxycarbonyl group (z) of the N-terminal end or by an (O-methyl)-fluoromethyl ketone group (fmk) of the C-terminal end.
- 13. The method according to claim 10, wherein the caspase inhibitor is an inhibitor of all caspases.
- 14. The method according to claim 13, wherein the inhibitor of caspases is tripeptide z-VAD-fmk.
- 15. The method according to claim 10, wherein the caspase inhibitor is an inhibitor of an initiator caspase.
- 16. The method according to claim 15, wherein the caspase inhibitor is caspase-2 or caspase-10.
- 17. The method according to claim 16, wherein the inhibitor of the initiator caspase-10 is peptide z-AEVD-fmk.
- 18. The method according to claim 16, wherein the inhibitor of the initiator caspase-2 is peptide z-VDVAD-fmk.
- 19. The method according to claim 10, wherein the caspase inhibitor is an inhibitor of an effector caspase.
- 20. The method according to claim 19, wherein the caspase inhibitor is an inhibitor of effector caspase-3.
- 21. The method according to claim 20, wherein the inhibitor of the effector caspase-3 is peptide z-DEVD-fmk.
- 22. The method according to claim 19, wherein the caspase inhibitor is an inhibitor of effector caspase-9.0.
- 23. The method according to claim 22, wherein the inhibitor of the effector caspase-9 is peptide z-LEHD-fmk.
- 24. The method according to claim 2, further comprising one or more additional inhibitors of retinal pericyte apoptosis.
- 25. The method according to claim 24, comprising at least two inhibitors of pericyte apoptosis selected from the group consisting of an antioxidant compound, an inhibitor of phosphatidylcholine-phospholipase C (PC-PLC), an inhibitor of acid sphingomyelinase, and a caspase inhibitor.
- 26. A pharmaceutical composition which treats and/or prevents diabetic retinopathy comprising as an active agent a therapeutically effective amount of at least one inhibitor of retinal pericyte apoptosis and a pharmaceutically acceptable carrier.
- 27. The pharmaceutical composition according to claim 26, wherein the active agent is an antioxidant compound and/or an inhibitor of phosphatidylcholine-phospholipase C and/or an inhibitor of acid sphingomyelinase, combined with at least one caspase inhibitor.
- 28. The pharmaceutical composition according to claim 26, wherein the active agent is contained in an amount of about 0.01 to about 200 mg/kg of body weight.
- 29. The pharmaceutical composition according to claim 26, comprising from about 5% to 95% (w/w) of active agent.
- 30. The pharmaceutical composition according to claim 26, in oral or injection form.
- 31. The pharmaceutical composition according to claim 30, comprising between about 0.01 and about 10% by weight of active agent.
- 32. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is an antisense oligonucleotide of 6 to 25 nucleotides complementary to part of a polynucleotide sequence which codes for a caspase, phosphatidylcholine-phospholipase C or acid sphingomyelinase.
- 33. The method according to claim 1, wherein the inhibitor of retinal pericyte apoptosis is a molecule of nucleic acid comprising at least one polynucleotide sequence coding for a peptide of 2 to 10 amino acids which is a competitive inhibitor of a caspase.
- 34. A method of identifying compounds capable of preventing or treating diabetic retinopathy comprising:
contacting a pericyte culture treated with AGE with a compound to be tested; and evaluating apoptosis of pericytes in the culture to determine capacity of said compound to prevent or treat diabetic retinopathy.
- 35. The method according to claim 34, wherein the compound is selected from the group consisting of antioxidants, inhibitors of the production of ceramides and/or DAG, caspase inhibitors and antisense oligonucleotides of 6 to 25 nucleotides complementary to a part of a polynucleotide sequence which codes for a caspase, phosphatidylcholine-phospholipase C, acid sphingomyelinase and nucleic acid molecules comprising at least one polynucleotide sequence coding for a peptide of 2 to 10 amino acids which is a competitive inhibitor of a caspase.
Priority Claims (1)
Number |
Date |
Country |
Kind |
00/13640 |
Oct 2000 |
FR |
|
RELATED APPLICATION
[0001] This is a continuation of PCT/FR01/03306 filed Oct. 26, 2001, which claims benefit from French Application No. 00/13640 filed Oct. 24, 2000.
Continuations (1)
|
Number |
Date |
Country |
Parent |
PCT/FR01/03306 |
Oct 2001 |
US |
Child |
10421389 |
Apr 2003 |
US |