# US 2010/0168047 A9 · Inhibition of apoptosis-specific eIF-5A ("eIF-5A1") with antisense oligonucleotides and siRNA as anti-inflammatory therapeutics

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- Number: US 2010/0168047 A9
- Document ID: US20100168047A9
- Status: Published application
- Kind: A9
- Application number: 11/134,445
- Filed: 2005-05-23
- Published: 2010-07-01
- Earliest claimed: 2001-07-23
- Inventors: John Thompson; Bruce Galton; Catherine Taylor; Charles Dinarello; Leonid Reznikov; Adrienne Boone; Marianne Hopkins
- Web page: https://patentgrep.com/patent/US20100168047A9

## 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 31/7088: Compounds having three or more nucleosides or nucleotides
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/53: partially self-complementary or closed
- 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

## Abstract

The present invention relates to apoptosis specific eucaryotic initiation factor 5A (eIF-5A), referred to as apoptosis-specific eIF-5A or eIF5A1, nucleic acids and polypeptides and methods for inhibiting or suppressing apoptosis in cells using antisense nucleotides or siRNAs to inhibit expression of apoptosis-specific eIF-5A. The invention also relates to suppressing or inhibiting expression of pro-inflammatory cytokines or inhibiting activation of NFKB by inhibiting expression of apoptosis-specific eIF-5A.

## Claims

### Claim 1

An antisense oligonucleotide of apoptosis-specific eIF-5A wherein said antisense oligonucleotide suppresses endogenous expression of apoptosis-specific eIF-5A in a cell.

### Claim 2 (depends on 1)

The antisense oligonucleotide of claim 1, wherein apoptosis-specific eIF-5A is encoded by nucleotide sequence of SEQ ID NO:20.

### Claim 3 (depends on 1)

The antisense oligonucleotide of claim 1, wherein apoptosis-specific eIF-5A is encoded by nucleotide sequence of SEQ ID NO:41.

### Claim 4 (depends on 1)

The antisense oligonucleotide of claim 1 wherein the antisense oligonucleotide has the sequence set forth in SEQ ID NO:35.

### Claim 5 (depends on 1)

The antisense oligonucleotide of claim 1 wherein the antisense oligonucleotide has the sequence set forth in SEQ ID NO:37.

### Claim 6 (depends on 1)

The antisense oligonucleotide of claim 1 wherein the antisense oligonucleotide has the sequence set forth in SEQ ID NO:39.

### Claim 7 (depends on 1)

An expression vector for the transfection of a mammalian cell comprising the antisense oligonucleotide of claim 1 and regulatory sequences operatively linked to the antisense oligonucleotide to allow transcription of said antisense oligonucleotide in said cell.

### Claim 8 (depends on 4)

An expression vector for the transfection of a mammalian cell comprising the antisense oligonucleotide of claim 4 and regulatory sequences operatively linked to the antisense oligonucleotide to allow transcription of said antisense oligonucleotide in said cell.

### Claim 9 (depends on 5)

An expression vector for the transfection of a mammalian cell comprising the antisense oligonucleotide of claim 5 and regulatory sequences operatively linked to the antisense oligonucleotide to allow transcription of said antisense oligonucleotide in said cell.

### Claim 10 (depends on 6)

An expression vector for the transfection of a mammalian cell comprising the antisense oligonucleotide of claim 6 and regulatory sequences operatively linked to the antisense oligonucleotide to allow transcription of said antisense oligonucleotide in said cell.

### Claim 11 (depends on 7)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the expression vector of claim 7 to said cell whereby said apoptosis-specific eIF-5A antisense oligonucleotide inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 12 (depends on 8, 9)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the expression vector of claim 8, 9, or 10 to said cell whereby said apoptosis-specific eIF-5A antisense oligonucleotide inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 13 (depends on 11)

The method of claim 11 wherein said inhibition of expression of endogenous apoptosis-specific eIF-5A in said cell has an effect on the cell selected from the group consisting of suppressing apoptosis in said cell, reducing expression of p53 in said cell, reducing levels of a cytokine produced in said cell, reducing levels of a cytokine produced in said cell, increasing expression of Bcl-2 in said cell; reducing levels of myeloperoxidase produced in said cell, reducing levels of active NFk beta in said cell, reducing levels of TLR4 in said cell, reducing levels of TNFR-1 in said cell and reducing levels of iNOS in said cell.

### Claim 14 (depends on 12)

The method of claim 12 herein said inhibition of expression of endogenous apoptosis-specific eIF-5A in said cell has an effect on the cell selected from the group consisting of suppressing apoptosis in said cell, reducing expression of p53 in said cell, reducing levels of a cytokine produced in said cell, reducing levels of a cytokine produced in said cell, increasing expression of Bcl-2 in said cell; reducing levels of myeloperoxidase produced in said cell, and reducing levels of active NFk beta in said cell, reducing levels of TLR4 in said cell, reducing levels of TNFR-1 in said cell and reducing levels of iNOS in said cell.

### Claim 15

A method delivering siRNA to lung cells of a mammal in vivo, the method comprising mixing said siRNA with water and delivering to a mammal intranasally.

### Claim 16

An siRNA of apoptosis-specific eIF-5A wherein said siRNA suppresses endogenous expression of apoptosis-specific eIF-5A in a cell.

### Claim 17 (depends on 16)

The siRNA of claim 16, wherein apoptosis-specific eIF-5A is encoded by nucleotide sequence of SEQ ID NO:20.

### Claim 18 (depends on 16)

The siRNA of claim 16, wherein apoptosis-specific eIF-5A is encoded by nucleotide sequence of SEQ ID NO:41.

### Claim 19 (depends on 16)

The siRNA of claim 16 wherein the siRNA has the sequence set forth in SEQ ID NO:30.

### Claim 20 (depends on 16)

The siRNA of claim 16 wherein the siRNA has the sequence set forth in SEQ ID NO:31.

### Claim 21 (depends on 16)

The siRNA of claim 16 wherein the siRNA has the sequence set forth in SEQ ID NO:32.

### Claim 22 (depends on 16)

The siRNA of claim 16 wherein the siRNA has the sequence set forth in SEQ ID NO:33.

### Claim 23 (depends on 16)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the siRNA of claim 16 to said cell whereby said apoptosis-specific eIF-5A siRNA inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 24 (depends on 19, 20, 21)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the siRNA of claim 19, 20, 21, or 22 to said cell whereby said apoptosis-specific eIF-5A siRNA inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 25 (depends on 16)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the siRNA of claim 16 to said cell whereby said apoptosis-specific eIF-5A siRNA inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 26 (depends on 19, 20, 21)

A method of inhibiting expression of apoptosis-specific eIF-5A in a cell, the method comprising administering the siRNA of claim 19, 20, 21, or 22 to said cell whereby said apoptosis-specific eIF-5A siRNA inhibits expression of endogenous apoptosis-specific eIF-5A in said cell.

### Claim 27 (depends on 25)

The method of claim 25 wherein said inhibition of expression of endogenous apoptosis-specific eIF-5A in said cell has an effect on the cell selected from the group consisting of suppressing apoptosis in said cell, reducing expression of p53 in said cell, reducing levels of a cytokine produced in said cell, reducing levels of a cytokine produced in said cell, increasing expression of Bcl-2 in said cell; reducing levels of myeloperoxidase produced in said cell, and reducing levels of active NFk beta in said cell, reducing levels of TLR4 in said cell, reducing levels of TNFR-1 in said cell and reducing levels of iNOS in said cell.

### Claim 28 (depends on 26)

The method of claim 26 herein said inhibition of expression of endogenous apoptosis-specific eIF-5A in said cell has an effect on the cell selected from the group consisting of suppressing apoptosis in said cell, reducing expression of p53 in said cell, reducing levels of a cytokine produced in said cell, reducing levels of a cytokine produced in said cell, increasing expression of Bcl-2 in said cell; reducing levels of myeloperoxidase produced in said cell, and reducing levels of active NFk beta in said cell, reducing levels of TLR4 in said cell, reducing levels of TNFR-1 in said cell and reducing levels of iNOS in said cell.