Methods to treat pulmonary fibrosis

Abstract

The present invention relates to compositions, methods, and kits for the treatment or prevention of fibrotic airway or lung conditions. In particular, the compositions, methods, and kits are particularly useful for the treatment or prevention of pulmonary fibrosis, such as idiopathic pulmonary fibrosis, but are not limited thereto. In one embodiment, the present invention provides a method for treating or preventing a fibrotic airway or lung condition in a subject requiring such treatment or prevention, the method comprising administering an antisense oligonucleotide (AON) that promotes the production of endogenous soluble RAGE to the subject, thereby treating or preventing a fibrotic airway or lung condition in the subject.

Claims

1. A method for treating or preventing a fibrotic airway or lung condition in a subject requiring such treatment, the method comprising administering to the subject an antisense oligonucleotide (AON) that promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE), thereby treating or preventing a fibrotic airway or lung condition in the subject.

2. A method for alleviating or improving symptoms of a fibrotic airway or pulmonary condition in a subject requiring such alleviation or improvement, the method comprising administering an antisense oligonucleotide (AON) that promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE) to the subject requiring such alleviation or improvement of symptoms of a fibrotic airway or pulmonary condition in the subject.

3. The use of antisense oligonucleotides (AONs) that promote the production of endogenous soluble RAGE and / or reduce the production of membrane-bound RAGE (mRAGE) in the manufacture of pharmaceuticals for the treatment or prevention of airway or lung conditions associated with fibrosis in subjects requiring such treatment or prevention.

4. The method or use according to any one of the prior claims, wherein the AON, which promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE), is administered directly to the airway and / or lungs.

5. The method or use according to any one of the prior claims, wherein the administration of AON promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE) in the whole airway, lower airway, or upper airway.

6. The method or use according to any one of the prior claims, wherein the method promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE) in the lower respiratory tract, preferably the lungs.

7. The method or use according to any one of the prior claims, wherein the antisense oligonucleotide (AON) that promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE) is administered by inhalation.

8. The method or use according to any one of the prior claims, wherein the antisense oligonucleotide (AON) that promotes the production of endogenous soluble RAGE and / or reduces the production of membrane-bound RAGE (mRAGE) is administered via intranasal administration.

9. The method or use according to any one of the prior claims, wherein the airway or lung condition accompanied by fibrosis is pulmonary fibrosis.

10. The method or use according to any one of the prior claims, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, familial pulmonary fibrosis, pulmonary fibrosis caused by sarcoidosis, pulmonary fibrosis caused by silicosis, pulmonary fibrosis caused by asbestososis, pulmonary fibrosis caused by coal miner's pneumoconiosis, pulmonary fibrosis caused by anthraxidosis, pulmonary fibrosis caused by hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious pathogens, pulmonary fibrosis caused by inhalation of harmful gases, aerosols, chemical dust, fumes, or vapors, or drug-induced interstitial lung disease.

11. The method or use according to any one of the prior claims, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

12. The method according to any one of claims 1 to 11, wherein the AON promotes the production of the endogenous soluble RAGE by promoting the inclusion of exon 9b and / or the exclusion of exon 10 (e.g., skipping).

13. The method according to any one of claims 1 to 11, wherein AON promotes splicing in RAGE premRNA, resulting in the inclusion of exon 9b and / or skipping of exon 10.

14. The method according to claim 12 or 13, wherein the administration of AON results in an increase in the level of RAGE_v1, preferably the level of RAGE_v1 mRNA, in one or more tissues of the airway.

15. The method according to any one of claims 1 to 14, wherein the AON is administered to the whole airway, the upper airway, or the lower airway.

16. The method according to any one of claims 1 to 15, wherein the AON is administered as an aerosol.

17. The method according to any one of claims 1 to 16, wherein the AON is administered in a single dose.

18. The method according to any one of claims 1 to 17, wherein the AON is administered via the same route of administration in the first, second, or further administration.

19. The method according to any one of claims 1 to 18, wherein the same AON is administered in each of the first, second, or further administrations.

20. The method according to any one of claims 1 to 19, wherein the AON is a 10 to 50 nucleotide AON containing a target sequence complementary to a region near or within the intron of the RAGE premRNA, and optionally, the AON is a 10 to 50 nucleotide AON containing a target sequence complementary to or adjacent to the splice site of the RAGE premRNA.

21. The method according to any one of claims 1 to 20, wherein the AON is 10 to 50 nucleotides containing a target sequence complementary to the RAGE premRNA, and the secondary structure of the mRNA is modified to influence the selection of a splice site.

22. The method according to any one of claims 1 to 21, wherein the AON is isolated or purified AON for inducing the exclusion (also known as skipping) of one or more exon sequences in the RAGE gene transcript or a portion thereof.

23. The method according to any one of claims 1 to 22, wherein the AON is isolated or purified AON for inducing the retention of an intron sequence in the RAGE gene transcript or a part thereof.

24. The method according to any one of claims 1 to 23, wherein the AON comprises at least one modified nucleotide.

25. The method according to any one of claims 1 to 24, wherein the AON is chemically modified to prevent degradation of the premRNA-AON complex, and preferably the chemical modification is selected from the group consisting of phosphorodiamidate morpholino oligomer (PMO), 2'-O-methylphosphorothioate oligonucleotide (2OMe), and 2'-O-methoxyethyl phosphorothioate oligonucleotide (2'-MOE), locked nucleic acid (LNA) modified AON, thermally stable twist intercalating nucleic acid (TINA), and peptide nucleic acid (PNA).

26. The method according to any one of claims 1 to 25, wherein the AON is conjugated to a portion for increasing its delivery, preferably a cell-permeable peptide (CPP), vivo-morpholino (VMO), or peptide phosphorodiamidate morpholino oligomer (PPMO).

27. The method according to any one of claims 1 to 26, wherein the AON contains, essentially consists of, or consists of, a nucleotide sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the target region of exon 10 of RAGE premRNA throughout the antisense oligonucleotide. Preferably, the 5'-most nucleotide of AON is at nucleotide position 88 or 114 of exon 10, or is located at nucleotide positions 88-114 of exon 10.

28. The method according to any one of claims 1 to 27, wherein the AON is 8 to 40 nucleotides long, 15 to 25 nucleotides long, or 18 nucleotides long.

29. The method according to any one of claims 1 to 28, wherein the AON is selected from the group including the sequences shown in any one of Tables 1a to 1d.

30. The method according to any one of claims 1 to 29, wherein the AON includes the nucleotide sequence shown in any one of sequence numbers 1 to 31 and 33, or a nucleotide sequence that is at least 85%, 90%, or 95% identical thereto.

31. The method according to claim 27, wherein the AON comprises the nucleotide sequence shown in SEQ ID NO: 11, 18, 19, or 20, or a nucleotide sequence that is at least 85%, 90%, or 95% identical thereto.

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