A novel peptide therapy for treatment of herpetic stromal keratitis

一种治疗疱疹性基质性角膜炎的新型肽疗法

• 批准号: 7512143
• 负责人: Partha S Bhattacharjee
• 金额: $ 15.88万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512143
• 关键词: Acyclovir; Alzheimer' s Disease; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Apolipoprotein E; Appearance; Atherosclerosis; Binding; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Combined Modality Therapy; Communicable Diseases; Cornea; Data; Development; Disease; Effectiveness; Event; Exhibits; Eye diseases; Failure; Gelatinase B; Genes; Goals; HIV; Heparan Sulfate Proteoglycan; Herpes Labialis; Herpesvirus 1; Herpetic Keratitis; Human; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Keratitis; Keratoplasty; Knock-in Mouse; LDL-Receptor Related Protein 1; Laboratories; Lead; Mediating; Modeling; Mononuclear; Mus; Nature; Outcome; Pain; Pathology; Patients; Peptides; Pharmaceutical Preparations; Property; Protein Isoforms; Proteins; Receptor Cell; Recurrence; Reporting; Resistance; Risk Factors; Role; Severities; Simplexvirus; Source; Susceptibility Gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Treatment Efficacy; Treatment Failure; Vascular Endothelial Growth Factors; Viral; Viral Drug Resistance; Virus; Vision; base; cytokine; genetic analysis; in vivo; in vivo Model; infectious disease model; inhibitor/antagonist; innovation; macrophage; mimetics; mouse model; novel; nucleoside analog; public health relevance; receptor binding; response; restoration

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：在一些有限的研究中，已显示两种源自人基因载脂蛋白E（apoE）的两个受体结合区的小模拟肽具有抗病毒和抗炎化疗特性。这些化学治疗性质尚未在任何体内感染性疾病模型中进行测试。因此，本研究建议使用疱疹性角膜基质炎（HSK）的体内小鼠眼部模型来评估这些肽的疗效。HSK是一种由HSV-1引起的角膜慢性免疫炎症性疾病，目前的抗病毒和抗炎治疗在大约30%的患者中失败，导致需要角膜移植。开发具有不同作用机制的新药至关重要。我们建议的主要目标是确定这两种apoE模拟物抗感染肽对HSV-1感染和炎症的治疗功效。此外，遗传分析表明，人apoE的同种型apoE 54在患有炎症性疾病如阿尔茨海默病和动脉粥样硬化以及感染如HIV和由HSV-1引起的唇疱疹的患者中的百分比显著更高。当apoe 54基因存在时，这些疾病中存在的炎症会明显更加严重。虽然apoE 54基因携带者比apoE 53基因携带者更易患炎症相关疾病，但我们假设apoE 53基因产物对HSK具有强效的抗炎和抗病毒作用。我们最近获得的数据强烈表明：（1）人apoE 54是HSK的危险因素;（2）来源于人apoE硫酸乙酰肝素蛋白聚糖（HSPG）结合区的抗病毒肽抑制原发性HSK。其他实验室已报道另一种衍生自人apoE的巨噬细胞受体结合区的肽具有抗炎作用。具体目的1将检验这两种基于apoE受体的肽在治疗HSK（a）C57 B1/6小鼠和（B）人apoE 54敲入小鼠中具有治疗功效的假设。特异性目的2将检验炎症细胞因子和细胞在小鼠角膜中响应于HSK的有效apoE模拟肽治疗而下调的假设，并将允许我们鉴定通过肽治疗改变的分子和细胞。还将在体内测试抗病毒肽对无环鸟苷抗性HSV-1的治疗功效（以证明这种抗病毒作用机制不同于核苷类似物抑制剂）。这些目标的成功完成将验证apoE模拟肽通过细胞受体介导的阻断有效治疗眼疱疹的假设，并将最终导致我们鉴定控制这些治疗事件的一些分子。这项研究的长期目标是开发一种新的治疗与这些抗病毒和抗炎肽的这种痛苦和潜在的致盲感染性眼病。公共卫生相关性：单纯疱疹性角膜基质炎（HSK）是一种由单纯疱疹病毒1型引起的角膜慢性炎症性疾病。它的复发性和患者对强化抗病毒和抗炎化疗药物的反应失败使得这种潜在的致盲性疾病难以治疗。我们建议研究两种小肽的抗病毒和抗炎特性用于治疗HSK的有效性。