Compositions and methods for treating diabetic retinopathy

Patent metadata

Field	Value
Publication number	US-2019093106-A1
Application number	US-201615765736-A
Country	US
Kind code	A1
Filing date	Oct 6, 2016
Priority date	Oct 6, 2015
Publication date	Mar 28, 2019
Grant date	—

Abstract

The application discloses compositions and methods for preventing and treating diabetic retinopathy. It is disclosed herein that an inhibitor of microRNA-let-7b administered to the eye of a subject in need thereof is useful for preventing and treating several problems associated with diabetic retinopathy and plays a role in vasculature stabilization, increasing retinal thickness, reducing retinal capillary dropout, diminishing microvascular leakage, preventing or treating hyperproliferation of microvascular cells, and stabilizing aberrant neovascularization. The invention includes the use of various kinds of inhibitors of microRNA-let-7b, including, but not limited to, an antagomir of miRNA-let-7b. A useful compound of the invention can be administered into the eye, including intravitreally. A useful antagomir is Dy547-mA(*)mA(*)mCmCmAmCmAmCmAmAmCmCmUmAmCmUmAmCmCmU(*) mC(*)mA (*)(3′-Chl).

First claim

What is claimed is:

1 . A method for treating a retinopathy, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of an inhibitor of micro RNA (miRNA) let-7b levels or activity.

2 . The method of claim 1 , wherein said inhibitor is a nucleic acid.

3 . The method of claim 2 , wherein said nucleic acid is an antagomir of miRNA let-7b.

4 . The method of claim 2 , wherein said nucleic acid comprises the sequence SEQ ID NO:1 or a biologically active homolog or fragment thereof.

5 . The method of claim 4 , wherein said nucleic acid comprising the sequence SEQ ID NO: 1 or a biologically active homolog of fragment thereof is modified.

6 . The method of claim 5 , wherein said modification is selected from the group consisting of a detectable label, phosphorothioate modification, 2′-O-methyl modification, 2′-O-methoxyethyl modification, 3′-cholesterol (chl) modification, and locked nucleic acid (LNA) modification.

7 . The method of claim 5 , wherein said nucleic acid comprises at least two modifications.

8 . The method of claim 6 , wherein said nucleic acid comprises at least one phosphorothioate modification.

9 . The method of claim 6 , wherein said nucleic acid comprises at least one 2′-O-methyl modification.

10 . The method of claim 6 , wherein said nucleic acid comprises at least one 2′-O-methoxyethyl modification.

11 . The method of claim 6 , wherein said nucleic acid comprises a 3′-chl modification.

12 . The method of claim 6 , wherein said nucleic acid comprises at least one LNA modification.

13 . The method of claim 6 , wherein said nucleic acid comprises a detectable label.

14 . The method of claim 8 , wherein said nucleic acid comprises five phosphorothioate modifications.

15 . The method of claim 9 , wherein said nucleic acid comprises a 2′-O-methyl modification at each nucleotide residue.

16 . The method of claim 12 , wherein said nucleic acid comprises an LNA at each nucleotide residue.

17 . The method of claim 5 , wherein said fragment is SEQ ID NO:2 or a modification thereof.

18 . The method of claim 1 , wherein said inhibitor is selected from the group consisting of Antagomir-let7b (ant-let7b), LNA-Chl antisense of let-7b, LNA antisense let-7b, MOE antisense let-7b, truncated ant-let7b, LNA-Chl antisense let-7b mini, LNA antisense let-7b mini, and MOE antisense let-7b mini.

19 . The method of claim 1 , wherein said pharmaceutical composition is administered intravitreally.

20 . The method of claim 1 , wherein said method stimulates vascular stabilization and an increase in retinal thickness.

21 . The method of claim 1 , wherein said method reduces hyperproliferation of microvascular cells, retinal capillary dropout, and microvascular leakage.

22 . The method of claim 1 , wherein said retinopathy is diabetic retinopathy.

23 . A method for inhibiting the effects of increased levels or activity of miRNA let-7b in a subject in need thereof, wherein said increased levels or activity are associated with an injury, disease, or disorder, said method comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of an inhibitor of miRNA let-7b levels or activity.

24 . The method of claim 23 , wherein said inhibitor is a nucleic acid comprising the sequence SEQ ID NO: 1 or a biologically active homolog or fragment thereof and said sequence is modified.

25 . The method of claim 23 , wherein said increased levels or activity of miRNA let-7b are associated with diabetic retinopathy.

26 . The method of claim 23 , wherein said injury, disease, or disorder is a microvasculature injury, disease or disorder.

27 . A kit for treating diabetic retinopathy, said kit comprising at least one inhibitor of claim 1 , an applicator, and an instructional material for the use thereof.

Assignees

• Univ Virginia Patent Foundation

Inventors

• Dey Bijan K
• Yates Paul Andrew

Classifications

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title

• C12Q2600/178

  miRNA, siRNA or ncRNA · CPC title

• C12N2310/315

  Phosphorothioates · CPC title