Claims for Patent: 10,703,787

Summary for Patent: 10,703,787

Title:	Norrin regulation of cellular production of junction proteins and use to treat retinal vasculature edema
Abstract:	A method of tightening inter-cellular junctions in retinal or choroidal vessel cells includes exposing the retinal or choroidal vessel cells to norrin and an anti-VEGF agent. Upon sufficient contact time, for norrin to selectively up-regulate gene expression of VE-cadherin or claudin-5 in the retinal or choroidal vessel cells, the inter-cellular junctions are tightened. The method is also suitable for treating retinal pigment epithelial cells in wet macular degeneration.
Inventor(s):	Trese; Michael T. (Novi, MI), Capone; Antonio (Novi, MI), Drenser; Kimberly (Novi, MI)
Assignee:	RETINAL SOLUTIONS LLC (Ann Arbor, MI)
Application Number:	16/182,252
Patent Claims:	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 to an eye containing the retinal vessel cells or the choroidal vessel cells an effective amount of an N-terminus norrin truncate having a polypeptide N-terminus cleavage relative to a native norrin protein of a maximum of 40 amino acid residues and retaining a cysteine-knot motif of the native norrin, or a norrin mutant that has at least 85% amino acid identity to SEQ. ID. NO. 1 and retains the cysteine-knot motif of the native norrin; administering in concert with said norrin 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 norrin 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 and said anti-VEGF agent to simultaneously suppress VEGF binding to the retinal vessel cells or the choroidal vessel cells. 2. The method of claim 1, wherein the administering step is by intraocular injection. 3. The method of claim 1, wherein the administering step is by systemic administration. 4. The method of claim 1, wherein the administering step is by topical administration. 5. The method of claim 1, wherein said subject is human. 6. 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. 7. 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 administering step. 8. The method of claim 1, wherein said norrin is an N-terminus norrin truncate that consists of: a polypeptide of SEQ ID. NO. 2. 9. The method of claim 1, wherein said norrin is a norrin mutant selected from the group consisting of SEQ ID. NO. 3, 5, 6, 7, 8, 9, 10, 11, 14, and 16. 10. The method of claim 1, wherein said norrin is recombinant. 11. 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 and claudin-5 to qualify a tightness of the inter-cellular junctions. 12. The method of claim 11, wherein said dye is an immunostain for claudin-5 or VE-cadherin. 13. The method of claim 11, wherein said dye is Evans Blue dye or fluoroscein.

Details for Patent 10,703,787

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2035-06-08
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	06/30/2006		2035-06-08
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	08/10/2012		2035-06-08
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	10/13/2016		2035-06-08
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	03/20/2018		2035-06-08