Compositions and Methods for Treating Vascular Permeability

• US 20080280811A1
• Filed: 02/16/2006
• Published: 11/13/2008
• Est. Priority Date: 02/24/2005
• Status: Active Grant

• Current Assignee: Joslin Diabetes Center Inc.
• Original Assignee: Joslin Diabetes Center Inc.
• Inventors: Aiello, Lloyd P., Feener, Edward P.
• Granted Patent: US 8,841,259 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Q 1/527 involving lyase
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention provides methods and composition for the treatment and diagnosis of disorders associated with excessive vascular permeability and edema.

Claims

1. A method of decreasing retinal vascular permeability in the eye of a subject, the method comprising administering to the subject a therapeutically effective amount of one or more of:

(i) an inhibitor of Carbonic Anhydrase-1 (CA-1) and/or Carbonic Anhydrase-2 (CA-2) signaling and optionally an inhibitor of Vascular Endothelial Growth Factor (VEGF) signalling;

(ii) an inhibitor of a kallikrein/kinin pathway; and

/or

(iii) a Complement-1 Inhibitor (C1-INH) agonist.

2. The method of claim 1, wherein the inhibitor of CA-1 and/or CA-2 signaling and the inhibitor of VEGF signalling are administered in a single composition.

3. The method of claim 1, wherein the administering is local administration to the eye of the subject.

4. The method of claim 3, wherein the local administration is by injection into the vitreous or aqueous humor of the eye.

5. The method of claim 3, wherein the inhibitor of CA-1 and/or CA-2 signaling and the inhibitor of VEGF signalling are administered as eye drops.

6. The method of claim 1, wherein the C1-INH agonist is a C1-INH polypeptide, polynucleotide, or biologically active fragment thereof.

7. A method of decreasing retinal vascular permeability in the eye of a subject, the method comprising administering to the subject a therapeutically effective amount of one or more of an inhibitor of Carbonic Anhydrase-1 (CA-1) and CA-2 signaling, wherein the inhibitor is administered locally by injection into the vitreous or aqueous humor of the eye of the subject.

8. A method of decreasing cerebral vascular permeability in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more of:

(i) an inhibitor of Carbonic Anhydrase-1 (CA-1) and/or CA-2 signaling and optionally an inhibitor of Vascular Endothelial Growth Factor (VEGF) signalling;

(ii) an inhibitor of a kallikrein/kinin pathway; and

/or (ii) a Complement-1 Inhibitor (C1-INH) agonist.

9. The method of claim 8, wherein the inhibitor of CA-1 and/or CA-2 signaling and the inhibitor of VEGF signalling are administered in a single composition.

10. The method of claim 8, wherein the administering is intrathecal.

11. The method of claim 8, wherein the C1-INH agonist is a C1-INH polypeptide, polynucleotide, or biologically active fragment thereof.

12. The use of one or more of:

(i) an inhibitor of Carbonic Anhydrase-1 (CA-1) and/or Carbonic Anhydrase-2 (CA-2) signaling and an inhibitor of Vascular Endothelial Growth Factor (VEGF) signalling;

(ii) an inhibitor of a kallikrein/kinin pathway;

or

(iii) a Complement-1 Inhibitor (C1-INH) polypeptide, polynucleotide, or biologically active fragment thereof,

in the preparation of a medicament for the treatment of excessive retinal vascular permeability.

13. The use of one or more of:

(i) an inhibitor of Carbonic Anhydrase-1 (CA-1) and/or Carbonic Anhydrase-2 (CA-2) signaling and an inhibitor of Vascular Endothelial Growth Factor (VEGF) signalling;

(ii) an inhibitor of a kallikrein/kinin pathway;

or

(iii) a Complement-1 Inhibitor (C1-INH) polypeptide, polynucleotide, or biologically active fragment thereof,

in the preparation of a medicament for the treatment of excessive cerebral vascular permeability.

14. A pharmaceutical composition comprising an inhibitor of Carbonic Anhydrase-1 (CA-1) and/or Carbonic Anhydrase-2 (CA-2) signaling and an inhibitor of Vascular Endothelial Growth Factor (VEGF) signalling, and a physiologically acceptable carrier.

15. The composition of claim 14, wherein the composition is adapted for injection into the vitreous or aqueous humor of a mammalian eye.

16. The composition of claim 14, wherein the composition is adapted for use as eye drops.

17. A pharmaceutical composition comprising a Complement-1 Inhibitor (C1-INH) polypeptide, polynucleotide, or biologically active fragment thereof, and a physiologically acceptable carrier, wherein the composition is adapted for injection into the vitreous or aqueous humor of a mammalian eye.

18. A pharmaceutical composition comprising a Complement-1 Inhibitor (C1-INH) polypeptide, polynucleotide, or biologically active fragment thereof, and a physiologically acceptable carrier, wherein the composition is adapted for use as eye drops.

19. A method of identifying a candidate compound for the treatment of a disorder associated with excessive vascular permeability, the method comprising:

providing an assay of carbonic anhydrase activity;

contacting the assay with a test compound; and

identifying a test compound that significantly inhibits one or both of Carbonic Anhydrase-1 (CA-1) or Carbonic Anhydrase-2 (CA-2) activity,

wherein a test compound that significantly inhibits carbonic anhydrase activity is a candidate compound for the treatment of the disorder.

20. A method of identifying a candidate compound for the treatment of a disorder associated with excessive vascular permeability, the method comprising:

providing a model of the disorder;

contacting the model with a test compound;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s); and

comparing the level of the protein or mRNA to a reference,

wherein a test compound that causes a significant difference in a level of the protein or mRNA as compared to the reference is a candidate compound for the treatment of diabetic retinopathy/retinal vascular permeability.

21. The method of claim 20, wherein the difference is the inverse of the difference shown in Table 2 for a disease state as compared to an unaffected individual.

22. A method of diagnosing a subject with a disorder associated with excessive vascular permeability, the method comprising:

providing a sample from the subject;

detecting a level of one or more of the proteins listed in Table 2 in the sample, or mRNA encoding the protein(s); and

comparing the level of the protein to a reference,

wherein a significant difference in a level of the protein or mRNA as compared to the reference indicates that the subject has a disorder associated with excessive vascular permeability.

26. The method of any of claims 22 to 24, wherein the sample is from the eye or the brain of the subject.

23. A method of determining whether a subject has progressive retinopathy, the method comprising:

providing a sample from the subject;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s), in the sample; and

comparing the level of the protein or mRNA to a reference,

wherein a significant difference in a level of the protein or mRNA as compared to the reference, indicates that the subject has progressive retinopathy.

24. A method of evaluating a treatment for a disorder associated with excessive vascular permeability, the method comprising providing a sample from the subject;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s), in the sample;

administering one or more doses of a treatment, and comparing the level of the protein or mRNA to a reference,

wherein a significant difference in a level of the protein or mRNA, e.g., an increase or decrease as shown in Table 2 for a disease state as compared to an unaffected individual, as compared to the reference indicates the efficacy of the treatment.

25. The method of claim 24, wherein the reference represents a level of the protein or mRNA prior to administration of the treatment.

27. A method of determining a subject'"'"'s risk for development of a sight-threatening complication of retinopathy, the method comprising providing a sample from the subject;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s), in the sample; and

comparing the level of the protein to a reference,

wherein a significant difference in a level of the protein or mRNA as compared to the reference indicates the subject'"'"'s risk of developing a sight-threatening complication of retinopathy.

30. The method of any of claims 27 to 29, wherein the sample is from the eye of the subject.

31. The method of any of claims 27 to 29, wherein the reference represents a level of the protein or mRNA in an unaffected subject.

32. The method of any of claims 27 to 29, wherein the reference represents a level of the protein or mRNA in an affected subject.

28. A method of determining when a treatment modality administered to a subject to treat a disorder associated with excessive vascular permeability can be stopped, the method comprising:

providing a sample from the subject;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s), in the sample;

comparing the level of the protein or mRNA to a reference,

wherein a level of the protein or mRNA that approaches the level of the protein or mRNA in the reference indicates whether the treatment can be stopped.

29. A method of determining when a treatment for a disorder associated with excessive vascular permeability should be initiated in a subject, the method comprising:

providing a sample from the subject, e.g., from the eye, e.g., the vitreous or aqueous humor, of the subject;

detecting a level of one or more of the proteins listed in Table 2, or mRNA encoding the protein(s), in the sample; and

comparing the level of the protein or mRNA to a reference,

wherein a significant difference in a level of the protein or mRNA as compared to the reference indicates whether the treatment should be initiated.