# US 7,745,420 B2 · Methods for increasing in vivo efficacy of oligonucleotides and inhibiting inflammation in mammals

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- Number: US 7,745,420 B2
- Document ID: US7745420B2
- Status: Granted
- Kind: B2
- Application number: 10/482,949
- Filed: 2002-07-08
- Published: 2005-02-10
- Granted: 2010-06-29
- Earliest claimed: 2001-07-06
- Assignees: Topigen Pharmaceutique Inc.
- Inventors: Paolo Renzi; Mustapha Allam; Zoulfia Allakhverdi
- Web page: https://patentgrep.com/patent/US7745420B2

## 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 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 19/16: Purine radicals
- C07H 19/23: Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12N 2310/315: Phosphorothioates
- C12N 2310/333: Modified A
- 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

The invention relates to the use of nucleotide substitutes for increasing the in vivo efficacy of nucleic acid molecules and also for inhibiting inflammation in mammals. More particularly, the present invention relates to the use of 2′6′diaminopurine (DAP) and analogs thereof per se in anti-inflammatory compositions, and also for preparing nucleic acid molecules having an increased in vivo physiological efficiency and a reduced toxicity as compared to conventional oligos. The invention is particularly useful for the preparation of antisense oligonucleotides for treating pulmonary/respiratory diseases such as cystic fibrosis, asthma, chronic bronchitis, chronic obstructive lung disease, eosinophilic bronchitis, allergies, allergic rhinitis, pulmonary fibrosis, adult respiratory distress syndrome, sinusitis, respiratory syncytial virus or other viral respiratory tract infection and cancer.

## Claims

### Claim 1

A method for increasing in vivo anti-inflammatory efficacy of an oligonucleotide comprising:
a. identifying an oligonucleotide to be administered to the respiratory system for decreasing inflammation therein in a mammal in need thereof, the oligonucleotide having at least one adenosine nucleotide, and
b. replacing the at least one adenosine nucleotide with a nucleotide substitute selected from the group consisting of 2-amino-2′-deoxyadenosine and salts thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein said nucleotide substitute is 2-amino-2′-deoxyadenosine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the oligonucleotide is an antisense oligonucleotide.

### Claim 4 (depends on 1)

The method of claim 1, wherein the inflammation is associated with one or more respiratory system diseases.

### Claim 5 (depends on 4)

The method of claim 4, wherein the respiratory system disease is a sickness associated with an inflammation of the lungs, the airways and/or the nose.

### Claim 6 (depends on 4)

The method of claim 4, wherein the respiratory system disease is selected from the group consisting of pulmonary fibrosis, adult respiratory distress syndrome, cystic fibrosis, chronic obstructive lung disease, chronic bronchitis, eosinophilic bronchitis, asthma, allergy, allergic rhinitis, sinusitis and hypereosinophilia.

### Claim 7 (depends on 1)

The method of claim 1, wherein the oligonucleotide is SEQ ID NO: 8.

### Claim 8 (depends on 1)

The method of claim 1, wherein the oligonucleotide has at least one mononucleotide linking residue selected from the group consisting of: methylphosphonate, phosphotriester, phosphorothioate, phosphodiester, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene (methylmino), methyleneoxy (methylimino), and phosphoramidate residues.

### Claim 9 (depends on 1)

The method of claim 1, wherein the resulting oligonucleotide decreases or inhibits airway hyper-responsiveness.

### Claim 10 (depends on 1)

The method of claim 1, wherein the oligonucleotide is for administration to the lung.