Use of Cell-Permeable Peptide Inhibitors of the JNK Signal Transduction Pathway for the Treatment of Various 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 sequences, chimeric peptides, or of nucleic acids encoding same as well as pharmaceutical compositions containing same, for the treatment of various diseases or disorders strongly related to JNK signaling.

1 . A method of treating a disease or disorder comprising administering to a subject in need of treatment thereof a pharmaceutical composition comprising a JNK inhibitor sequence comprising less than 150 amino acids in length, wherein the disease or disorder is selected from the group consisting of
 (a) Mild Cognitive Impairment,   (b) intraocular inflammation following anterior and/or posterior segment surgery;   (c) wet or dry age-related macular degeneration and cataracts,   (d) eye inflammatory diseases,   (e) cancer and tumor diseases,   (f) diseases of the mouth and/or the jaw bone,   (g) Addison's disease, Agammagiobulinemia, Alopecia areata, Amytrophic lateral sclerosis, Antiphospholipid syndrome, Atopic allergy, Autoimmune aplastic anemia, Autoimmune cardiomyopathy, Autoimmune enteropathy, Autoimmune hemolytic anemia, Autoimmune inner ear, disease, Autoimmune lymphoproliferative syndrome, Autoimmune polyendocrine syndrome, Autoimmune progesterone dermatitis, Idiopathic thrombocytopenic purpura, Autoimmune urticaria, Balo concentric sclerosis, Bullous pemphigoid, Castleman's disease, Cicatricial pemphigoid, Cold agglutinin disease, Complement component 2 deficiency associated disease, Cushing's syndrome, Dagos disease, Adiposis dolorosa, Eosinophilic pneumonia, Epidermolysis bullosa acquisita, Hemolytic disease of the newborn, Cryoglobulinemia, Evans syndrome, Fibrodysplasia ossificans progressive, Gastrointestinal pemphigoid, Goodpasture's syndrome, Hashimoto's encephalopathy, Gestational pemphigoid, Hughes-stovin syndrome, Hypogammaglobulinemia, Lambert-eaton myasthenic syndrome, Lichen sclerosus, Morphea,  Pityriasis  lichenoides et  varioliformis acuta , Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus syndrome, Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria, Parry-romberg syndrome, Pernicious anemia, POEMS syndrome, Pyoderma gangrenosum, Pure red cell aplasia, Raynaud's phenomenon, Restless legs syndrome, Retroperitoneal fibrosis, Autoimmune polyendocrine syndrome type 2, Stiff person syndrome, Susac's syndrome, Febrile neutrophilic dermatosis, Sydenham's chorea, Thrombocytopenia, vitiligo,   (h) arthritis,   (i) skin diseases,   (j) tauopathies, amyloidoses and prion diseases,   (k) polypes,   (l) inflammatory diseases of the mouth or the jaw bone,   (m) osteonecrosis,   (n) encephalomyelitis,   (o) fibrotic diseases and/or disorders,   (p) kidney diseases and/or disorders,   (q) sympathetic ophthalmia,   (r) transplant rejection reaction,   (s) Corticobasal degeneration, progressive supranuclear palsy, schizophrenia, inherited Kreutzfeld Jacob, motor neurone disease, spinocerebellar ataxia/atrophie, dementia,   (t) and a hereditary or non-hereditary metabolic disease.   
     
     
         2 . The method according to  claim 1 , wherein the disorder/disease is intraocular inflammation following anterior and/or posterior segment surgery, wherein the surgery is selected from the group consisting of cataract surgery, laser eye surgery, glaucoma surgery, refractive surgery, corneal surgery, vitreo-retinal surgery, eye muscle surgery, oculoplastic surgery, ocular oncology surgery, conjunctival surgery including pterygium, and/or surgery involving the lacrimal apparatus. 
     
     
         3 . The method according to  claim 2 , wherein the JNK inhibitor is injected at a dose range selected from the Croup consisting of in the range of 0.01 μg/eye to 10 mg/eye, 0.1 μg/eye to 5 mg/eye, 1 μg/eye to 2 mg/eye, 100 μg/eye to 1.5 mg/eye, and 500 μg/eye to 1 mg/eye. 
     
     
         4 . The method according to  claim 3 , wherein the JNK inhibitor is injected is by instillation, intravitreally or subconjunctivally. 
     
     
         5 . The method according to  claim 4 , wherein the JNK inhibitor is applied is by a single injection within three hours after surgery. 
     
     
         6 . The method according to  claim 1 , wherein the disease is retinopathy. 
     
     
         7 . The method according to  claim 1 , wherein the disease is psoriasis. 
     
     
         8 . The method according to  claim 1 , wherein the disease is periodontitis. 
     
     
         9 . The method according to  claim 1 , wherein the disease is a graft rejection or transplant rejection reaction. 
     
     
         10 . The method according to  claim 1 , wherein the disease is glomerulonephritis. 
     
     
         11 . The method according to  claim 1 , wherein the disease liver cancer, prostate cancer, colon cancer. 
     
     
         12 . A method of reducing the likelihood of transplant rejection, comprising applying to the tissue being transplanted a pharmaceutical composition comprising a JNK inhibitor sequence comprising less than 150 amino acids in length prior its transplantation. 
     
     
         13 . The method according to  claim 12 , wherein the tissue being transplanted is a kidney, heart, lung, pancreas, liver, blood cell, bone marrow, cornea, accidental severed limb, face, nose, bone, cardiac valve, blood vessel or intestine transplant. 
     
     
         14 . The method of  claim 1 , wherein the JNK inhibitor sequence comprises a range of 5 to 150 amino acid residues. 
     
     
         15 . The method of  claim 1 , wherein the JNK inhibitor sequence binds c-jun amino terminal kinase (JNK). 
     
     
         16 . The method of  claim 1 , wherein the JNK inhibitor sequence inhibits the activation of at least one JNK targeted transcription factor when the JNK inhibitor sequence is present in a JNK expressing cell. 
     
     
         17 . The method of  claim 16 , wherein the JNK targeted transcription factor is selected from the group consisting of c-Jun, ATF2, and Elkl. 
     
     
         18 . The method of  claim 1 , wherein the JNK inhibitor sequence alters a JNK effect when the peptide is present in a JNK expressing cell. 
     
     
         19 . The method of  claim 1 , wherein the JNK inhibitor sequence is composed of L-amino acids, D-amino acids, or a combination of both. 
     
     
         20 . The method of  claim 1 , wherein the JNK inhibitor sequence comprises a fragment the amino acid sequence of SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104 or SEQ ID NO: 105. 
     
     
         21 . The method of  claim 1 , wherein the JNK inhibitor sequence comprises or consists of at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 13 to 20 and 33 to 100, or a fragment, derivative or variant thereof. 
     
     
         22 . The method of  claim 1 , wherein the JNK inhibitor sequence is covalently linked to a trafficking sequence. 
     
     
         23 .- 37 . (canceled)