Two small mimetic peptides derived from two receptor binding regions of the human gene apolipoprotein E (apoE) have been shown, in a few limited studies, to have anti-viral and anti-inflammatory chemotherapeutic properties. These chemotherapeutic properties have not been tested in any in vivo infectious disease model. Therefore, this study proposes to use an in vivo mouse ocular model of herpetic stromal keratitis (HSK) to assess the efficacy of these peptides. HSK is a chronic, immuno-inflammatory disease of the cornea caused by HSV-1, and current anti-viral and anti-inflammatory therapies fail in approximately 30% of patients, resulting in the need for corneal transplantation. Development of new drugs with different mechanisms of action is critical. The major goal of our proposal is to determine the therapeutic efficacy of these two apoE-mimetic, anti-infective peptides against HSV-1 infection and inflammation. Additionally, genetic analyses have shown that an isoform of human apoE, apoE 54, is found in a significantly greater percentage of patients with inflammatory diseases such as Alzheimer's and atherosclerosis, and infections such as HIV and cold sores caused by HSV-1. Inflammation, present in each of these diseases, is measurably more severe when the apoE 54 gene is present. While it is well established that carriers of apoE 54 gene are more susceptible to inflammation-related diseases than their apoE 53-carrying counterparts, we hypothesize that apoE 53 gene products will manifest potent anti-inflammatory and antiviral actions against HSK. We recently obtained data that strongly suggest that (1) human apoE 54 is a risk factor for HSK;and (2) an antiviral peptide derived from the heparan sulfate proteoglycan (HSPG) binding region of human apoE inhibits primary HSK. Another peptide derived from the macrophage receptor binding region of human apoE has been reported by other laboratories to be anti-inflammatory.
Specific Aim 1 will test the hypothesis that these two apoE receptor- based peptides have a therapeutic efficacy in the treatment of HSK (a) in C57Bl/6 mice and (b) in human apoE 54 knock-in mice.
Specific Aim 2 will test the hypothesis that inflammatory cytokines and cells are down- regulated in mice corneas in response to effective apoE mimetic peptide treatment for HSK, and will allow us to identify molecules and cells altered by the peptide therapy. The therapeutic efficacy of the anti-viral peptide will also be tested in vivo against acyclovir-resistant HSV-1 (to demonstrate that this antiviral mechanism of action is different than the nucleoside analogue inhibitors). Successful completion of these aims will validate the hypothesis that apoE mimetic peptides are effective in treating ocular herpes through cell-receptor mediated blocking, and will ultimately lead us to the identification of some of the molecules controlling these therapeutic events. The long-term goal of this study is to develop a novel therapy with these antiviral and anti- inflammatory peptides for this painful and potentially blinding infectious eye disease.
Herpetic stromal keratitis (HSK) is a chronic inflammatory disease of the cornea caused by herpes simplex virus-1. Its recurrent nature and patients'failure to respond to intensive anti- viral and anti-inflammatory chemotherapeutics make this potentially blinding disease difficult to treat. We propose to investigate the effectiveness of two small peptides for their anti-viral and anti-inflammatory properties for the treatment of HSK.
