US 2009/0263323 A1 · Novel means and methods for the treatment of hearing loss and phantom hearing

Abstract

This invention relates to a method of identifying a modulator of an NADPH oxidase, whereby said modulator is suitable as a lead compound and/or as a medicament for the treatment and/or prevention of hearing loss and/or phantom hearing, the method comprising the steps of (a) contacting a test compound with a protein, wherein said protein (i) comprises or consists of the amino acid sequence of any one of SEQ ID NO: 1, 3 or 5, or (ii) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO: 2, 4, 6, 23 or 24, or (iii) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or (iv) has a sequence at least 75% identical with the protein according to (i) or (ii) or with the fragment according to (iii) and exhibits NADPH oxidase activity, and optionally with one or more NADPH oxidase subunits, under conditions allowing binding of said test compound to said protein or, if present, said subunit(s); (b) optionally determining whether said test compound binds to said protein or, if present, said subunit(s); and (c) determining whether (ca) said test compound, upon contacting in step (a); or (cb) said test compound, upon binding in step (b) modulates the expression and/or activity of said protein or, if present, said subunit(s). Also provided are pharmaceutical compositions, medical uses and diagnostic uses of compounds of the invention.

Claims40

Dependent claims

A method of identifying a modulator of an NADPH oxidase, whereby said modulator is suitable as a lead compound and/or as a medicament for the treatment and/or prevention of hearing loss and/or phantom hearing, the method comprising the steps of

(a) contacting a test compound with a protein, wherein said protein
(i) comprises or consists of the amino acid sequence of any one of SEQ ID NO:
1, 3 or 5, or
(ii) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO:
2, 4, 6, 23 or 24, or
(iii) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or
(iv) has a sequence at least 95% identical with the protein according to (i) or (ii) or with the fragment according to (iii) and exhibits NADPH oxidase activity,
under conditions allowing binding of said test compound to said protein;
and
(b) determining whether said test compound, upon contacting in step (a) modulates the expression and/or activity of said protein.

7 more elements

A pharmaceutical composition comprising

(a) an antibody, aptamer, or a fragment or derivative thereof binding specifically a protein that:
(i) comprises or consists of the amino acid sequence of any one of SEQ ID NO:
1, 3 or 5 or
(iii) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO:
2, 4, 6, 23 or 24, or
(iii) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or
(iv) has a sequence at least 95% identical with the protein according to (i) or (ii) or with the fragment according to (iii) and exhibits NADPH oxidase activity;
(b) an antisense nucleic acid, an siRNA, or a ribozyme binding specifically a nucleic acid encoding said protein;
(c) a compound comprising the fragment of SEQ ID NO:
11 from position 202 to position 212, the fragment of SEQ ID NO:
11 from position 402 to position 463, the fragment of SEQ ID NO:
15 from position 200 to position 210, the fragment of SEQ ID NO:
15 from position 457 to position 513, the fragment of SEQ ID NO:
7 from position 158 to position 217, the fragment of SEQ ID NO:
7 from position 233 to position 289, the fragment of SEQ ID NO:
7 from position 321 to position 331, the fragment of SEQ ID NO:
19 from position 156 to position 216, the fragment of SEQ ID NO:
19 from position 226 to position 286, the fragment of SEQ ID NO:
19 from position 360 to position 370, wherein said compound may furthermore comprise a cell-penetrating peptide;
(d) a nucleic acid comprising a sequence encoding any of the fragments according to (c), wherein said nucleic acid may optionally comprise a sequence encoding a cell-penetrating peptide;
(e) aryliodonium compounds such as diphenylene iodonium (DPI), di-2-thienyliodonium, phenoxaiodonium;
(f) naphthoquinones such as plumbagin, acetylshikonin;
(g) inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin;
(h) gliotoxin;
(i) phenothiazines such as phenothiazine, trifluoperazine, and/or
(j) a derivative of any one of (e) to (i).

23 more elements

A pharmaceutical composition comprising

(a) an ototoxic agent;
and
(b) a compound selected from the group consisting of:
(i) an antibody, aptamer, or a fragment or derivative thereof binding specifically a protein that:
A) comprises or consists of the amino acid sequence of any one of SEQ ID NO:
1, 3 or 5, or
B) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO:
2, 4, 6, 23 or 24, or
C) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or
D) has a sequence at least 95% identical with the protein according to (A) or (B) or with the fragment according to (C) and exhibits NADPH oxidase activity,
(ii) an antisense nucleic acid, an siRNA, or a ribozyme binding specifically a nucleic acid encoding said protein;
(iii) a compound comprising the fragment of SEQ ID NO:
11 from position 202 to position 212, the fragment of SEQ ID NO:
11 from position 402 to position 463, the fragment of SEQ ID NO:
15 from position 200 to position 210, the fragment of SEQ ID NO:
15 from position 457 to position 513, the fragment of SEQ ID NO:
7 from position 158 to position 217, the fragment of SEQ ID NO:
7 from position 233 to position 289, the fragment of SEQ ID NO:
7 from position 321 to position 331, the fragment of SEQ ID NO:
19 from position 156 to position 216, the fragment of SEQ ID NO:
19 from position 226 to position 286, the fragment of SEQ ID NO:
19 from position 360 to position 370, wherein said compound may furthermore comprise a cell-penetrating peptide;
(iv) a nucleic acid comprising a sequence encoding any of the fragments according to (c), wherein said nucleic acid may optionally comprise a sequence encoding a cell-penetrating peptide;
(v) aryliodonium compounds such as diphenylene iodonium (DPI), di-2-thienyliodonium, phenoxaiodonium;
(vi) naphthoquinones such as plumbagin, acetylshikonin;
(vii) inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin;
(viii) gliotoxin;
(ix) phenothiazines such as phenothiazine, trifluoperazine, and/or
(x) a derivative of any one of (v) to (ix).

26 more elements

A method for the treatment and/or prevention of hearing loss and/or phantom hearing comprising administering an effective amount of a modulator of an NADPH oxidase to a subject afflicted with hearing loss and/or phantom hearing, wherein said modulator is selected from the group consisting of

(a) an antibody, aptamer, or a fragment or derivative thereof binding specifically said protein;
(b) an antisense nucleic acid, an siRNA, or a ribozyme binding specifically a nucleic acid encoding said protein;
(c) a known modulator of NOX3 and/or NADPH oxidases and/or electron transport proteins wherein said known modulator is selected from the group consisting of:
(i) aryliodonium compounds such as diphenylene iodonium (DPI), di-2-thienyliodonium, phenoxaiodonium;
(ii) ortho-methoxy-substituted catechols such as apocynin, acetosyringone, vanillin, vanillic acid, syringaldehyde, syringic acid;
(iii) naphthoquinones such as plumbagin, acetylshikonin;
(iv) inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin;
(v) gliotoxin;
(vi) phenothiazines such as phenothiazine, trifluoperazine;
and
(vii) a derivative of any one of (i) to (vi).
(d) a compound comprising the fragment of SEQ ID NO:
11 from position 202 to position 212, the fragment of SEQ ID NO:
11 from position 402 to position 463, the fragment of SEQ ID NO:
15 from position 200 to position 210, the fragment of SEQ ID NO:
15 from position 457 to position 513, the fragment of SEQ ID NO:
7 from position 158 to position 217, the fragment of SEQ ID NO:
7 from position 233 to position 289, the fragment of SEQ ID NO:
7 from position 321 to position 331, the fragment of SEQ ID NO:
19 from position 156 to position 216, the fragment of SEQ ID NO:
19 from position 226 to position 286, the fragment of SEQ ID NO:
19 from position 360 to position 370, wherein said compound may furthermore comprise a cell-penetrating peptide;
and
(e) a nucleic acid comprising a sequence encoding any of the fragments according to
(d), wherein said nucleic acid may optionally comprise a sequence encoding a cell-penetrating peptide
wherein the NADPH oxidase:
(1) comprises or consists of the amino acid sequence of any one of SEQ ID NO:
1, 3 or 5, or
(2) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO:
2, 4, 6, 23 or 24, or
(3) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or
(4) has a sequence at least 95% identical with the protein according to (1) or (2) or with the fragment according to (3) and exhibits NADPH oxidase activity.

29 more elements

A method for the diagnosis of hearing loss and/or phantom hearing and/or an individual's disposition or risk to develop said loss and/or said phantom hearing in an individual afflicted or suspected of being inflicted with such a disorder, wherein the method comprises administering to such an individual an effective amount of a compound binding to an NADPH oxidase or subunit thereof, wherein said NADPH oxidase:

(1) comprises or consists of the amino acid sequence of any one of SEQ ID NO:
1, 3 or 5, or
(2) is encoded by a nucleic acid comprising or consisting of the sequence of any one of SEQ ID NO:
2, 4, 6, 23 or 24, or
(3) is a fragment of the protein according to (i) or (ii) and exhibits NADPH oxidase activity, or
(4) has a sequence at least 95% identical with the protein according to (1) or (2) or with the fragment according to (3) and exhibits NADPH oxidase activity,
and wherein said compound is selected from the group consisting of
(a) an antibody, aptamer, or a fragment or derivative thereof binding specifically said protein;
and
(b) a known modulator of NOX3 and/or NADPH oxidases and/or electron transport proteins, wherein said known modulator is selected from the group consisting of:
(i) aryliodonium compounds such as diphenylene iodonium (DPI), di-2-thienyliodonium, phenoxaiodonium;
(ii) ortho-methoxy-substituted catechols such as apocynin, acetosyringone, vanillin, vanillic acid, syringaldehyde, syringic acid;
(iii) cisplatin, hydrogen hexachloroplatinate;
(iv) naphthoquinones such as plumbagin, acetylshikonin;
(v) inhibitors of HMG-CoA reductase including statins such as lovastatin, simvastatin, atorvastatin;
(vi) gliotoxin;
(vii) phenothiazines such as phenothiazine, trifluoperazine;
and
(viii) a derivative of any one of (i) to (vii).

16 more elements

Dependencies are inferred from the claim text.

Novel means and methods for the treatment of hearing loss and phantom hearing

Life of this patent

Novel means and methods for the treatment of hearing loss and phantom hearing

Life of this patent

Abstract

Claims40