# US 8,772,262 B2 · Preventive or therapeutic agent for fibrosis

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- Number: US 8,772,262 B2
- Document ID: US8772262B2
- Status: Granted
- Kind: B2
- Application number: 13/824,080
- Filed: 2011-10-14
- Published: 2013-08-22
- Granted: 2014-07-08
- Earliest claimed: 2010-10-14
- Assignees: Mie University; Otsuka Pharmaceutical Co., Ltd.
- Applicants: Esteban C Gabazza; Tetsu Kobayashi; Hidekazu Toyobuku; Ayako Fukuda; Tetsuya Hasegawa
- Inventors: Esteban C Gabazza; Tetsu Kobayashi; Hidekazu Toyobuku; Ayako Fukuda; Tetsuya Hasegawa
- Web page: https://patentgrep.com/patent/US8772262B2

## CPC

- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 21/02: with ribosyl as saccharide radical
- 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)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2320/30: Special therapeutic applications
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Provided is siRNA effective for the treatment of fibrosis and a pharmaceutical containing the siRNA. An siRNA having a full length of 30 or fewer nucleotides and targeting a sequence consisting of 17 to 23 consecutive bases selected from the group consisting of bases at positions 1285 to 1318, bases at positions 1398 to 1418, bases at positions 1434 to 1463, bases at positions 1548 to 1579, bases at positions 1608 to 1628, bases at positions 1700 to 1726, bases at positions 1778 to 1798, bases at positions 1806 to 1826, and bases at positions 1887 to 1907 of SEQ ID NO: 1.

## Claims

### Claim 1

An siRNA having a full length of 30 or fewer nucleotides and selected from the group consisting of
an siRNA comprising a sense sequence of SEQ ID NO: 2 and an antisense sequence of SEQ ID NO: 3;
an siRNA comprising a sense sequence of SEQ ID NO: 6 and an antisense sequence of SEQ ID NO: 7;
an siRNA comprising a sense sequence of SEQ ID NO: 8 and an antisense sequence of SEQ ID NO: 9;
an siRNA comprising a sense sequence of SEQ ID NO: 24 and an antisense sequence of SEQ ID NO: 25; and
an siRNA comprising a sense sequence of SEQ ID NO: 54 and an antisense sequence of SEQ ID NO: 55.

### Claim 2 (depends on 1)

The siRNA according to claim 1, wherein 1 to 10 consecutive nucleotides excluding an overhang nucleotide from a 3′ terminus of a sense strand of the siRNA are converted into DNA.

### Claim 3 (depends on 1)

The siRNA according to claim 1, wherein 1 to 10 consecutive nucleotides from a 5′ terminus of an antisense strand of the siRNA are converted into DNA.

### Claim 4 (depends on 1)

The siRNA according to claim 1, wherein 1 to 10 consecutive nucleotides excluding an overhang nucleotide from a 3′ terminus of a sense strand of the siRNA are converted into DNA and 1 to 10 consecutive nucleotides from a 5′ terminus of an antisense strand of the siRNA are converted into DNA.

### Claim 5 (depends on 1)

The siRNA according to claim 1, wherein a 5′ terminus of an antisense strand is monophosphorylated.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising the siRNA according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 7 (depends on 1)

A method for inhibiting TGF-β1 gene expression, the method comprising:
administering an effective amount of the siRNA according to claim 1 to a human or animal in need thereof.

### Claim 8 (depends on 1)

A method for preventing or treating fibrosis, the method comprising:
administering an effective amount of the siRNA according to claim 1 to a human or animal in need thereof.

### Claim 9 (depends on 1)

A method for preventing or treating pulmonary fibrosis or lung cancer, the method comprising:
administering an effective amount of the siRNA according to claim 1 to a human or animal in need thereof.

### Claim 10 (depends on 1)

A method for producing a TGF-β1 gene expression inhibitor, the method comprising:
expressing the siRNA according to claim 1.

### Claim 11 (depends on 1)

The siRNA according to claim 1, wherein a 5′ terminus of an antisense strand is monothiophosphorylated.

### Claim 12 (depends on 1)

The siRNA according to claim 1, which comprises a sense sequence of SEQ ID NO: 2 and an antisense sequence of SEQ ID NO: 3.

### Claim 13 (depends on 1)

The siRNA according to claim 1, which comprises a sense sequence of SEQ ID NO: 6 and an antisense sequence of SEQ ID NO: 7.

### Claim 14 (depends on 1)

The siRNA according to claim 1, which comprises a sense sequence of SEQ ID NO: 8 and an antisense sequence of SEQ ID NO: 9.

### Claim 15 (depends on 1)

The siRNA according to claim 1, which comprises a sense sequence of SEQ ID NO: 24 and an antisense sequence of SEQ ID NO: 25.

### Claim 16 (depends on 1)

The siRNA according to claim 1, which comprises a sense sequence of SEQ ID NO: 54 and an antisense sequence of SEQ ID NO: 55.

### Claim 17 (depends on 1)

The siRNA according to claim 1, wherein all or a part of a 3′ overhang of a sense strand is converted into DNA.

### Claim 18 (depends on 17)

The siRNA according to claim 17, wherein 1 to 10 consecutive nucleotides excluding an overhang nucleotide from a 3′ terminus of a sense strand of the siRNA are converted into DNA and 1 to 10 consecutive nucleotides from a 5′ terminus of an antisense strand of the siRNA are converted into DNA.

### Claim 19

An siRNA having a full length of 30 or fewer nucleotides and targeting a sequence of 17 to 23 consecutive bases selected from the group consisting of positions 1285 to 1305 of SEQ ID NO: 1 and positions 1398-1418 of SEQ ID NO: 1.