Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of chronic or non-chronic inflammatory eye diseases

Abstract

The present invention refers to the use of protein kinase inhibitors and more specifically to the use of inhibitors of the protein kinase c-Jun amino terminal kinase, JNK inhibitor (poly-)peptides, chimeric peptides, or of nucleic acids encoding same as well as pharmaceutical compositions containing same, for the treatment of non-chronic or chronic inflammatory eye diseases, such as inflammatory diseases of the blephara, conjunctiva, cornea, sclera, the vitreous body, uvea, ciliary body, choroid, orbital bone, lacrimal gland, or iris, in particular wherein the inflammatory disease is selected from hordeolum, chalazion, conjunktivitis, keratitis, scieritis, episcleritis, endophthalmitis, panophtalmitis, irititis, uveitis, cyclitis, chorioiditis, orbital phlegmon, and myositis of the eye muscle etc.

1 . A method of treating a chronic or non-chronic inflammatory eye disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a c-Jun N-terminal kinase (JNK) inhibitor (poly-)peptide comprising from 5 to 150 amino acid residues. 
     
     
         2 . The method of  claim 1 , wherein the JNK inhibitor (poly-)peptide comprises from 10 to 100 amino acid residues. 
     
     
         3 . The method of  claim 1 , wherein the JNK inhibitor (poly-)peptide comprises from 10 to 75 amino acid residues. 
     
     
         4 . The method of  claim 1 , wherein the JNK inhibitor (poly-)peptide comprises from 10 to 50 amino acid residues. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the JNK inhibitor (poly-)peptide is composed of L-amino acids, D-amino acids, or a combination of both, comprising, at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 D- and/or L-amino acids, wherein the D- and/or L-amino acids are arranged in the JNK inhibitor (poly-)peptide in a blockwise, a non-blockwise or in an alternate manner. 
     
     
         8 . The method of  claim 1 , wherein the JNK inhibitor (poly-)peptide comprises a fragment, variant, or variant of such fragment of a human or rat IB1 (poly-)peptide having the sequence of SEQ ID NO: 103 or 104, or being encoded by SEQ ID NO: 102 or 105. 
     
     
         9 . The method of  claim 1 , wherein the inhibitor sequence comprises or consists of at least one amino acid sequence according to SEQ ID NOs: 1 to 4, 13 to 20 and 33 to 100, or a fragment, derivative or variant thereof. 
     
     
         10 . A method of treating a chronic or non-chronic inflammatory eye disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a chimeric (poly-)peptide comprising at least one first domain and at least one second domain linked by a covalent bond, the first domain comprising a trafficking (poly-)peptide, and the second domain comprising a JNK inhibitor (poly-)peptide comprising from 5 to 150 amino acid residues. 
     
     
         11 . The method of  claim 10 , wherein the chimeric (poly-)peptide is composed of L-amino acids, D-amino acids, or a combination of both, comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 D- and/or L-amino acids, wherein the D- and/or L-amino acids may be arranged in the chimeric peptide in a blockwise, a non-blockwise or in an alternate manner. 
     
     
         12 . The method of  claim 10 , wherein the trafficking (poly-)peptide comprises the amino acid sequence of a human immunodeficiency virus TAT polypeptide. 
     
     
         13 . The method of  claim 10 , wherein the trafficking sequence consists of or comprises the amino acid sequence of SEQ ID NO: 5, 6, 7, 8, 21 or 22. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The method of  claim 10 , wherein the chimeric (poly-)peptide consists of or comprises the amino acid sequence of any of SEQ ID NOs: 9 to 12 and 23 to 32, or a fragment, or variant thereof. 
     
     
         17 . The method of  claim 10 , wherein the chimeric (poly-)peptide consists of or comprises the amino acid sequence of SEQ ID NO: 9 or 11. 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The method of  claim 10 , wherein the pharmaceutical composition is to be administered by an administration route selected from the group consisting of parenteral routes, including intravenous, intramuscular, subcutaneous, intradermal, transdermal, enteral routes, including orally, rectally, topical routes, including nasal, intranasal, other routes, including epidermal or patch delivery, and local administration to the eye, in particular intravitreous administration, subconjunctival administration and/or instillation. 
     
     
         23 . The method of  claim 10 , wherein the non-chronic or chronic inflammatory eye disease is selected from inflammatory diseases of the blephara, conjunctiva, cornea, sclera, the vitreous body, uvea, ciliary body, choroid, orbital bone, lacrimal gland, or iris, in particular wherein the inflammatory disease is selected from hordeolum, chalazion, conjunktivitis, keratitis, scleritis, episcleritis, endophthalmitis, panophtalmitis, irititis, uveitis, cyclitis, chorioiditis, orbital phlegmon, and myositis of the eye muscle. 
     
     
         24 . The method of  claim 10 , wherein a dose (per kg bodyweight) of the JNK inhibitor (poly-)peptide and/or chimeric (poly-)peptide is in the range of up to 10 mmol/kg. 
     
     
         25 . The method of  claim 10 , wherein a dose of the JNK inhibitor (poly-)peptide and/or chimeric (poly-)peptide is in the range of from about 1 pmol/kg to about 1 mmol/kg, from about 10 pmol/kg to about 0.1 mmol/kg, from about 10 pmol/kg to about 0.01 mmol/kg, from about 50 pmol/kg to about 1 μmol/kg, from about 100 pmol/kg to about 500 nmol/kg, from about 200 pmol/kg to about 300 nmol/kg, from about 300 pmol/kg to about 100 nmol/kg, from about 500 pmol/kg to about 50 nmol/kg, from about 750 pmol/kg to about 30 nmol/kg, from about 250 pmol/kg to about 5 nmol/kg, from about 1 nmol/kg to about 10 nmol/kg, or a combination of any two of said values. 
     
     
         26 . The method of  claim 10 , wherein the inflammatory eye disease is uveitis and wherein the (poly-)peptide consists of or comprises the amino acid sequence of SEQ ID NO: 11, or consists of or comprises a amino acid sequence having a sequence identity of at least 30%, 50%, 70%, 80%, 90%, 92% or 95% with SEQ ID NO: 11. 
     
     
         27 . The method of  claim 1 , wherein the pharmaceutical composition is administered by an administration route selected from the group consisting of parenteral routes, including intravenous, intramuscular, subcutaneous, intradermal, transdermal, enteral routes, including orally, rectally, topical routes, including nasal, intranasal, other routes, including epidermal or patch delivery, and local administration to the eye, in particular intravitreous administration, subconjunctival administration and/or instillation. 
     
     
         28 . The method of  claim 1 , wherein the non-chronic or chronic inflammatory eye disease is selected from inflammatory diseases of the blephara, conjunctiva, cornea, sclera, the vitreous body, uvea, ciliary body, choroid, orbital bone, lacrimal gland, or iris, and the inflammatory disease is selected from hordeolum, chalazion, conjunktivitis, keratitis, scleritis, episcleritis, endophthalmitis, panophtalmitis, irititis, uveitis, cyclitis, chorioiditis, orbital phlegmon, and myositis of the eye muscle. 
     
     
         29 . The method of  claim 1 , wherein a dose (per kg bodyweight) of the JNK inhibitor (poly-)peptide and/or chimeric (poly-)peptide is in the range of up to 10 mmol/kg. 
     
     
         30 . The method of  claim 1 , wherein a dose of the JNK inhibitor (poly-)peptide and/or chimeric (poly-)peptide is in the range of from about 1 pmol/kg to about 1 mmol/kg, from about 10 pmol/kg to about 0.1 mmol/kg, from about 10 pmol/kg to about 0.01 mmol/kg, from about 50 pmol/kg to about 1 μmol/kg, from about 100 pmol/kg to about 500 nmol/kg, from about 200 pmol/kg to about 300 nmol/kg, from about 300 pmol/kg to about 100 nmol/kg, from about 500 pmol/kg to about 50 nmol/kg, from about 750 pmol/kg to about 30 nmol/kg, from about 250 pmol/kg to about 5 nmol/kg, from about 1 nmol/kg to about 10 nmol/kg, or a combination of any two of said values. 
     
     
         31 . The method of  claim 1 , wherein the inflammatory eye disease is uveitis and wherein the (poly-)peptide consists of or comprises the amino acid sequence of SEQ ID NO: 11, or consists of or comprises a amino acid sequence having a sequence identity of at least 30%, 50%, 70%, 80%, 90%, 92% or 95% with SEQ ID NO: 11.