# US 10,870,852 B2 · Compositions and methods for treating diabetic retinopathy

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- Number: US 10,870,852 B2
- Document ID: US10870852B2
- Status: Granted
- Kind: B2
- Application number: 15/765,736
- Filed: 2016-10-06
- Published: 2019-03-28
- Granted: 2020-12-22
- Earliest claimed: 2015-10-06
- Assignees: University of Virginia Patent Foundation
- Applicants: University of Virginia Patent Foundation
- Inventors: Bijan K. Dey; Paul Andrew Yates
- Web page: https://patentgrep.com/patent/US10870852B2

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2310/3517: Marker; Tag
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/158: Expression markers
- C12Q 2600/178: miRNA, siRNA or ncRNA
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## 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).

## Claims

### Claim 1

A method for treating a retinopathy, said method comprising providing a subject suffering from a retinopathy in which stabilization of vasculature in an eye of the subject is desired; and intravitreally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of an inhibitor of micro RNA (miRNA) let-7b levels or activity.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 2)

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

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 5)

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

### Claim 8 (depends on 6)

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

### Claim 9 (depends on 6)

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

### Claim 10 (depends on 6)

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

### Claim 11 (depends on 6)

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

### Claim 12 (depends on 6)

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

### Claim 13 (depends on 6)

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

### Claim 14 (depends on 8)

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

### Claim 15 (depends on 9)

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

### Claim 16 (depends on 12)

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

### Claim 17 (depends on 5)

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

### Claim 18 (depends on 1)

The method of claim 1, wherein said inhibitor is selected from the group consisting of Antagomir-let7b which comprises Dy547 mA(*)mA(*)mCmCmAmCmAmCmAmAmCmCmUmAmCmUmAmCmCmU(*)mC(*)mA(*) (3′-Chl), LNA-Chl anti-sense let-7b which comprises IAIAICICIAICIAICIAIAICICIUIAICIUIAICICIUICIA(3′-Chl), LNA anti-sense let-7b which comprises IAIAICICIAICIAICIAIAICICIUIAICIUIAICICIUICIA, MOE anti-sense let-7b which comprises meAmeAmeCmeCmeAmeCmeAmeCmeAmeAmeCmeCmeUmeAmeCmeUmeAmeCme CmeUmeCmeA, Antagomir let-7b mini (truncated version) which comprises mA(*)mA(*)mCmCmAmCmAmCmAmAmCmC(*)mU(*)mA(3′-Chl), LNA-Chl anti-sense let-7b mini which comprises IAIAICICIAICIAICIAIAICICIUIA (3′-Chl), LNA anti-sense let-7b mini which comprises IAIAICICIAICIAICIAIAICICIUIA, and MOE anti-sense let-7b mini which comprises meAmeAmeCmeCmeAmeCmeAmeCmeAmeAmeCmeCmeUmeA, wherein Dy547 is a fluorescent molecule; “m” indicates 2-O-Methyl moiety; * indicates phosphorothioate; (3′-Chl) indicates a cholesterol molecule at the 3′; “I” indicates LNA modification; and “me” indicates 2′-O-methoxyethyl modification.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

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

### Claim 21 (depends on 1)

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

### Claim 22

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 a microvasculature injury, disease, or disorder of the eye, said method comprising providing a subject in which stabilization of vasculature in an eye of the subject is desired; and intravitreally 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.

### Claim 23 (depends on 22)

The method of claim 22, 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.

### Claim 24 (depends on 22)

The method of claim 22, wherein said increased levels or activity of miRNA let-7b are associated with diabetic retinopathy.