Peptides and Peptide Mimetics to Treat Pathologies Associated With Eye Disease

Abstract

This invention provides novel active agents (e.g. peptides, small organic molecules, amino acid pairs, etc.) peptides that ameliorate one or more symptoms of eye disease and/or other pathologies characterized by an inflammatory response. In certain embodiment, the peptides resemble a G* amphipathic helix of apolipoprotein J. The agents are highly stable and readily administered via an oral route or via intraocular injection.

1 . A method for treating a subject with eye disease, the method comprising administering to the subject in need thereof an effective amount of one or more of the active agents described in Tables 2-18, and/or a small organic molecule as described herein in an amount sufficient to ameliorate one or more symptoms of said condition. 
     
     
         2 . The method of  claim 1 , wherein said active agent is a polypeptide comprising the amino acid sequence of 4F (SEQ ID NO:5). 
     
     
         3 . The method of  claim 1 , wherein said administration is by a route selected from the group consisting of oral administration, nasal administration, rectal administration, intraperitoneal injection, and intravascular injection, intraocular injection, intravitreal injection, subconjuctival injection, peri-/retrobulbar injection, subcutaneous injection, eye drops, eye gel, eye ointment, spray, emulsion, suspension, transcutaneous administration, and intramuscular injection, via any drug carriers as sponges, contact lenses, polymers, microspheres, implants, pellets, and genetically engineered cells. 
     
     
         4 . The method of  claim 1 , wherein said active agent is administered in conjunction with a antiangiogenic agents. 
     
     
         5 . The method of  claim 1 , wherein the eye disease is selected from the group comprising macular degeneration, age related maculopathy (ARM), age related macular degeneration (AMD) including both the dry and wet forms of age related macular degeneration, glaucoma, ocular hypertension, macular edema, retinal pigment epithelium detachments, coats disease, uveitis, sicca syndrome, hereditary diseases associated with increased extra-/intracellular lipid storage/accumulation, and juvenile macular degeneration. 
     
     
         6 . A method of ameliorating a symptom of eye disease, the method comprising administering to the subject to the subject in need thereof an effective amount of one or more of the active agents described in Tables 2-18, and/or a small organic molecule as described herein in an amount sufficient to ameliorate one or more symptoms of said condition. 
     
     
         7 . The method of  claim 13  wherein the symptom is selected from the group comprising accumulation of extracellular lipids in Bruch's membranes, accumulation of lipid rich debris, vision loss, formation of choriocapillaris, thickening of the Bruch's membrane, accumulation of neutral lipids in the Bruch's membrane, formation of a diffusion barrier between the retinal pigment epithelium and choriocapillaris, deposition of debris (basal linear deposits and drusen) between the basal membrane of the RPE, and the inner collagenous layer, accumulation of lipofuscin in the RPE cells, RPE atrophy, photoreceptor degeneration, choroidal neovascularization, as well as leakage, bleeding, scarring of the eye 
     
     
         8 . The method of  claim 13 , wherein the eye disease is selected from the group comprising macular degeneration, age related maculopathy (ARM), age related macular degeneration (AMD) including both the dry and wet forms of age related macular degeneration, glaucoma, ocular hypertension, macular edema, retinal pigment epithelium detachments, coats disease, uveitis, sicca syndrome, hereditary diseases associated with increased extra-/intracellular lipid storage/accumulation, and juvenile macular degeneration, 
     
     
         9 . A method of ameliorating a symptom of eye disease, the method comprising administering to the subject an effective amount of a peptide wherein said peptide: ranges in length from about 18 to 37 amino acids and comprises at least 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), 1 tyrosine (Y); wherein said peptide forms a class A amphipathic helix; comprises at least one “D” amino acid residue; and protects a phospholipid against oxidation by an oxidizing agent. 
     
     
         10 . The method of  claim 9 , wherein said peptide further comprises a protecting group coupled to the amino or carboxyl terminus. 
     
     
         11 . The method of  claim 9 , wherein said peptide further comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus. 
     
     
         12 . The method of  claim 10 , wherein said protecting groups are independently selected from the group consisting of acetyl, amide, and 3 to 20 carbon alkyl groups, Fmoc, Tboc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl-Z),2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Born), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Burn), t-butoxy (tBuO), t-Butyl (tBu), Acetyl (Ac), and Trifluoroacetyl (TFA). 
     
     
         13 . The method of  claim 9 , wherein all enantiomeric amino acids are “D” amino acids. 
     
     
         14 . The method of  claim 9 , wherein said peptide is mixed with a pharmacologically acceptable excipient. 
     
     
         15 . The method of  claim 9 , wherein said peptide is mixed with a pharmacologically acceptable excipient suitable for oral administration to a mammal. 
     
     
         16 . The method of  claim 9 , wherein said peptide comprises an amino acid sequence selected from the group consisting of D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:1191),-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 1192), D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-P-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F (SEQ ID NO: 1193),-D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO:1194), D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F-P-D-K-L-K-A-F-Y-D-K-V-F-E-W-L-K-E-A-F (SEQ ID NO:1195), D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L-P-D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L (SEQ ID NO:1196), D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-P-D-W-F-K-A-FY-D-K-V-A-E-K-F-K-E-A-F—(SEQ ID NO: 1197), or the reverse of any of these sequences. 
     
     
         17 . The method of  claim 16 , wherein said peptide comprises a protecting group coupled to the amino terminal and said amino terminal protecting group is a protecting group selected from the group consisting of acetyl, propeonyl, and a 3 to 20 carbon alkyl. 
     
     
         18 . The method of  claim 16 , wherein said peptide comprises a protecting group coupled to the carboxyl terminal and said carboxyl terminal protecting group is an amide. 
     
     
         19 . The method of  claim 16 , wherein said peptide comprises: a first protecting group coupled to the amino terminus wherein said protecting group is a protecting group selected from the group consisting of acetyl, propeonyl, and a 3 to 20 carbon alkyl;
 and a second protecting group coupled to the carboxyl terminal and said carboxyl terminal protecting group is an amide.   
     
     
         20 . The method of  claim 9 , wherein said oxidizing agent is selected from the group consisting of hydrogen peroxide, 13(S)-HPODE, 15(S)-HPETE, HPODE, HPETE, HODE, and HETE. 
     
     
         21 . The method of  claim 9 , wherein said phospholipid is selected from the group consisting of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (PEIPC), 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (SAPC), 1-stearoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (SOVPC), 1-stearoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (SGPC), 1-stearoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (SEIPC), 1-stearoyl-2-arachidonyl-sn-glycero-3-phosphorylethanolamine (Ox-SAPE),1-stearoyl-2-oxovaleroyl-sn-glycero-3-phosphorylethanolamine (SOVPE),1-stearoyl-2-glutaroyl-sn-glycero-3-phosphorylethanolamine (SGPE), and 1-stearoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylethanolamine (SEI PE). 
     
     
         22 . Use of an active agent described in Tables 2-18, and/or a small organic molecule as described herein in a treatment of macular degeneration. 
     
     
         23 . A method for treating a subject with eye disease, the method comprising administering to the subject in need thereof an effective amount of one or more of the active agents described in Tables 2-18, and/or a small organic molecule as described herein in an amount sufficient to ameliorate one or more symptoms of said condition in combination with an anti-angiogenic therapy. 
     
     
         24 . The method of  claim 23 , wherein the anti-angiogenic therapy is selected from the list consisting of pegaptanib (Macugen™ by Pfizer), ranibizumab (Lucentis™ by Genentech) bevacizumab (Avastin™ by Genentech), carboxyamidotriazole, TNP-470, CM101, IFN-a, IL-12, platelet factor 4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids+heparin, cartilage-derived angiogenesis inhibitory factor, matrix metallopreteinase inhibitors, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, prolactin, α v β 3  inhibitors, and linomide, VEGF-Trap (by Regeneron Pharmaceuticals), Aminosterols (Evizion® by Genera Corp.), Cortisen (Retaane® by Alcon), tyrosine kinase inhibitors, anti-angiogenic siRNA, inhibitors of the complement system, gentherapeutic therapies (e.g. AdPEDF.11 by Genvec). 
     
     
         25 . A method of ameliorating a symptom of eye disease, the method comprising administering to the subject to the subject in need thereof an effective amount of one or more of the active agents described in Tables 2-18, and/or a small organic molecule as described herein in an amount sufficient to ameliorate one or more symptoms of said condition in combination with an anti-angiogenic therapy. 
     
     
         26 . The method of  claim 25 , wherein the anti-angiogenic therapy is selected from the list consisting of pegaptanib (Macugen™ by Pfizer), ranibizumab (Lucentis™ by Genentech) bevacizumab (Avastin™ by Genentech), carboxyamidotriazole, TNP-470, CM101, IFN-a, IL-12, platelet factor 4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids+heparin, cartilage-derived angiogenesis inhibitory factor, matrix metallopreteinase inhibitors, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, prolactin, α v β 3  inhibitors, and linomide., VEGF-Trap (by Regeneron Pharmaceuticals), Aminosterols (Evizion® by Genera Corp.), Cortisen (Retaane® by Alcon), tyrosine kinase inhibitors, anti-angiogenic siRNA, inhibitors of the complement system, gentherapeutic therapies (e.g. AdPEDF.11 by Genvec).