Norrin regulation of cellular production of junction proteins and use to treat retinal vasculature edema

1. A method of treating edema in a retina of a living subject by tightening inter-cellular junctions in retinal vessel cells or choroidal vessel cells defining a tissue comprising:

administering by intraocular injection or solution droplets application to an eye containing the retinal vessel cells or the choroidal vessel cells an effective amount of an N-terminus norrin truncate that has a polypeptide N-terminus cleavage relative to a native norrin protein of up 40 amino acid residues retaining a cysteine-knot motif of the native norrin and capable of binding to the retinal vessel cells or the choroidal vessel cells, or a norrin mutant having at least 85% amino acid identity to SEQ ID NO. 1 and retaining a cysteine-knot motif of the native norrin and capable of binding to the retinal vessel cells or the choroidal vessel cells; and

allowing sufficient time for said N-terminus norrin truncate or said norrin mutant to selectively up-regulate gene expression of VE-cadherin and claudin-5 in the retinal vessel cells or the choroidal vessel cells to tighten the inter-cellular junctions of the tissue for prevention of vascular leakage or repair of the vascular leakage to treat the edema in the retina.

2. The method of claim 1 , wherein said subject is human.

3. The method of claim 1 , wherein said subject is one of: cow, horse, sheep, pig, goat, chicken, cat, dog, mouse, guinea pig, hamster, rabbit, or rat.

4. The method of claim 1 , further comprising diagnosing retina edema associated with fluid leakage from a retinal vessel defined by retinal vessel cells prior to the exposing step.

5. The method of claim 1 , wherein said N-terminus norrin truncate consists of: a polypeptide of SEQ ID. NO. 2.

6. The method of claim 1 , wherein said N-terminus norrin truncate or norrin mutant is selected from the group consisting of SEQ ID. NO. 3, 5, 6, 7, 8, 9, 10, 11, 14, and 16.

7. The method of claim 1 , wherein said N-terminus norrin truncate or norrin mutant is selected from the group consisting of SEQ ID. NO. 12, 13, 14, 15, 17, 18, 19, 20, and 21.

8. The method of claim 1 , wherein said N-terminus norrin truncate or said norrin mutant is recombinant.

9. The method of claim 1 , further comprising bringing a dye into contact with the retinal vessel cells after the allowing sufficient time for said norrin to selectively up-regulate gene expression of VE-cadherin or claudin-5 to measure a tightness of the inter-cellular junctions.

10. The method of claim 9 , wherein said dye is an immunostain for claudin-5 or VE-cadherin.

11. The method of claim 9 , wherein said dye is Evans Blue dye or fluoroscein.

12. The method of claim 1 wherein the tissue is experiencing edema prior to the administering step.

13. A method of treating edema in a retina of a living subject by tightening inter-cellular junctions in retinal vessel cells or choroidal vessel cells defining a tissue comprising:

administering by intraocular injection or solution droplets application to an eye containing the retinal vessel cells or the choroidal vessel cells an effective amount of an N-terminus norrin truncate that has a polypeptide N-terminus cleavage relative to a native norrin protein of up 40 amino acid residues retaining a cysteine-knot motif of the native norrin and capable of binding to the retinal vessel cells or the choroidal vessel cells, or a norrin mutant having at least 85% amino acid identity to SEQ ID NO. 1 and retaining a cysteine-knot motif of the native norrin and capable of binding to the retinal vessel cells or the choroidal vessel cells;

administering in concert with said N-terminus norrin truncate or norrin mutant and by intraocular injection or solution droplets application to the eye containing the retinal vessel cells or the choroidal vessel cells an effective amount an anti-VEGF agent selected from the group consisting of: bevacizumab, ranibizumab, lapatinib, sunitinib, sorafenib, axitinib, pazopanib, or a combination thereof and

allowing sufficient time for said N-terminus norrin truncate or said norrin mutant to selectively up-regulate gene expression of VE-cadherin and claudin-5 in the retinal vessel cells or the choroidal vessel cells to tighten the inter-cellular junctions of the tissue for prevention of vascular leakage or repair of the vascular leakage to treat the edema in the retina.