Topical delivery of therapeutic agents using cell-penetrating peptides for the treatment of age-related macular degeneration and other eye diseases

Abstract

The present disclosure provides therapeutic agents for the treatment of age-related macular degeneration (AMD) and other eye disorders. One or more therapeutic agents can be used to treat any stages (including the early, intermediate and advance stages) of AMD, and any phenotypes of AMD, including geographic atrophy (including non-central GA and central GA) and neovascularization (including types 1, 2 and 3 NV). In some embodiments, the one or more therapeutic agents are or include an anti-dyslipidemic agent, an antioxidant, an anti-inflammatory agent, a complement inhibitor, a neuroprotector or an anti-angiogenic agent, or any combination thereof. In certain embodiments, the one or more therapeutic agents are or include an anti-dyslipidemic agent (e.g., an apolipoprotein mimetic or/and a statin). In some embodiments, the one or more therapeutic agents are mixed with, non-covalently associated with or covalently bonded to a cell-penetrating peptide (CPP), encapsulated in CPP-conjugated nanoparticles, micelles or liposomes, or modified (e.g., stapled, prenylated, lipidated or coupled to a small-molecule α-helix mimic) to acquire membrane-translocating ability. In certain embodiments, the one or more therapeutic agents are administered by eye drop.

What is claimed is: 
     
         1 . A transepithelial, transmembrane or transmucosal drug-delivery system (TDS) comprising a therapeutic agent and a cell-penetrating peptide (CPP), wherein:
 the therapeutic agent is an anti-dyslipidemic agent, an antioxidant, an anti-inflammatory agent, a complement inhibitor or a neuroprotector; and   the TDS is capable of delivering the therapeutic agent into the eye.   
     
     
         2 . The TDS of  claim 1 , which is capable of delivering the therapeutic agent into the posterior segment (e.g., the vitreous or/and the retina) of the eye. 
     
     
         3 . The TDS of  claim 1  or  2 , which is capable of delivering the therapeutic agent into the eye when administered by an eye drop or a contact lens (e.g., a corneal lens or a scleral lens). 
     
     
         4 . The TDS of any one of the preceding claims, wherein the therapeutic agent is an apoA-I mimetic (e.g., L-4F or D-4F), an apoE mimetic (e.g., AEM-28-14) or a statin (e.g., atorvastatin or simvastatin). 
     
     
         5 . The TDS of any one of the preceding claims, wherein the CPP is a polycationic CPP (e.g., the peptide for ocular delivery [POD]). 
     
     
         6 . The TDS of any one of the preceding claims, wherein the CPP is an arginine-rich CPP, such as a polyarginine (e.g., hexa-arginine or nona-arginine) or a TAT-related CPP [e.g., TAT(49-57)]. 
     
     
         7 . The TDS of any one of  claims 1  to  4 , wherein the CPP is an amphipathic CPP (e.g., Pep-1 or penetratin). 
     
     
         8 . The TDS of any one of  claims 1  to  4 , wherein the CPP is a hydrophobic CPP. 
     
     
         9 . The TDS of any one of the preceding claims, wherein the therapeutic agent is mixed with or non-covalently associated with the CPP. 
     
     
         10 . A pharmaceutical composition comprising a therapeutic agent, a cell-penetrating peptide (CPP) and one or more pharmaceutically acceptable carriers or excipients, wherein the therapeutic agent is an anti-dyslipidemic agent, an antioxidant, an anti-inflammatory agent, a complement inhibitor or a neuroprotector. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the therapeutic agent is an apoA-I mimetic (e.g., L-4F or D-4F), an apoE mimetic (e.g., AEM-28-14) or a statin (e.g., atorvastatin or simvastatin). 
     
     
         12 . The pharmaceutical composition of  claim 10  or  11 , wherein the CPP is an arginine-rich CPP {e.g., a polyarginine [e.g., hexa-arginine or nona-arginine] or a TAT-related CPP [e.g., TAT(49-57)]} or an amphipathic CPP (e.g., Pep-1 or penetratin). 
     
     
         13 . The pharmaceutical composition of any one of  claims 10  to  12 , wherein the therapeutic agent is mixed with or non-covalently associated with the CPP. 
     
     
         14 . The pharmaceutical composition of any one of  claims 10  to  13 , which is formulated for administration by an eye drop or a contact lens (e.g., a corneal lens or a scleral lens). 
     
     
         15 . A method of treating an eye disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of the transepithelial, transmembrane or transmucosal drug-delivery system (TDS) of any one of  claims 1  to  9  or the pharmaceutical composition of any one of  claims 10  to  14 . 
     
     
         16 . The method of  claim 15 , wherein the eye disorder is atrophic or neovascular age-related macular degeneration. 
     
     
         17 . The method of  claim 15  or  16 , further comprising administering one or more additional therapeutic agents. 
     
     
         18 . A method of treating an eye disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of a therapeutic agent listed in Table 1, wherein the therapeutic agent is delivered into the eye using a cell-penetrating peptide or/and a chemical penetration enhancer. 
     
     
         19 . The method of  claim 18 , wherein the therapeutic agent is delivered into the eye by means of an eye drop or a contact lens (e.g., a corneal lens or a scleral lens). 
     
     
         20 . The method of  claim 18  or  19 , wherein the eye disorder is atrophic or neovascular age-related macular degeneration. 
     
     
         21 . The method of any one of  claims 18  to  20 , further comprising administering one or more additional therapeutic agents.