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: 7945287
• 负责人: Partha S Bhattacharjee
• 金额: $ 18.29万
• 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 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945287
• 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，来自人类基因载脂蛋白E(ApoE)的两个受体结合区的两个小的模拟多肽已被证明具有抗病毒和抗炎的化疗特性。这些化疗特性还没有在任何体内感染疾病模型中进行测试。因此，本研究建议使用疱疹间质角膜炎(HSK)的在体小鼠眼部模型来评估这些多肽的疗效。HSK是一种由HSV-1引起的慢性免疫性角膜炎症性疾病，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个载脂蛋白E类似物、抗感染多肽对HSV-1感染和炎症的治疗效果。此外，遗传分析表明，在阿尔茨海默氏症和动脉粥样硬化等炎症性疾病以及艾滋病毒和HSV-1引起的冻疮等感染患者中，发现人类载脂蛋白E的一种亚型apoE 54的比例要高得多。当apoE 54基因存在时，这些疾病中存在的炎症可以测量到更严重。虽然载脂蛋白E 54基因携带者比其载脂蛋白E 53基因携带者更容易患炎症相关疾病，但我们推测载脂蛋白E 53基因产物将显示出强大的抗炎和抗病毒作用。我们最近获得的数据有力地表明：(1)人载脂蛋白E 54是HSK的危险因素；(2)从人载脂蛋白E的硫酸乙酰肝素蛋白多糖(HSPG)结合区衍生的一种抗病毒多肽抑制原发HSK。另一种来源于人载脂蛋白E巨噬细胞受体结合区的多肽已被其他实验室报道具有抗炎作用。具体目的1将验证这两个基于apoE受体的多肽对HSK(A)在C57BL/6小鼠和(B)在人apoE 54基因敲除小鼠中具有治疗效果的假设。《特殊目的2》将验证有效的apoE模拟多肽治疗HSK后，炎症细胞因子和细胞在小鼠角膜中下调的假设，并将使我们能够识别多肽治疗所改变的分子和细胞。该抗病毒多肽的治疗效果还将在体内测试对阿昔洛韦耐药的HSV-1(以证明这种抗病毒的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载脂蛋白E模拟肽通过细胞受体介导的阻断治疗眼部疱疹有效的假设，并最终将使我们识别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方法，使用这些抗病毒和抗炎肽来治疗这种疼痛和潜在致盲的感染性眼病。公共卫生相关性：单纯疱疹病毒性角膜炎(HSK)是由单纯疱疹病毒1型引起的一种慢性角膜炎症性疾病。它的复发性质和患者对强化抗病毒和抗炎化疗药物的反应失败，使这种潜在的致盲疾病难以治疗。我们建议研究两种小肽的抗病毒和抗炎作用，以治疗HSK。