Development of a novel anti-inflammatory treatment for clinical management of end

开发一种新型抗炎治疗方法用于临床管理终末期

• 批准号: 7611495
• 负责人: Rafal A Farjo
• 金额: $ 22.73万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611495
• 关键词: Address; Adjuvant Therapy; Adverse effects; Affect; Age related macular degeneration; Albumins; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Bacteria; Basic Science; Binding; Blindness; Blood-Retinal Barrier; Cataract Extraction; Cell Adhesion Molecules; Cells; Clinical; Clinical Management; Complement Activation; Complication; Data; Development; Dexamethasone; Dimerization; Disease; Distant; Dose; Electroretinography; Endophthalmitis; Endotoxins; Experimental Models; Extravasation; Eye; Gatifloxacin; Gene Expression; Genes; Genus staphylococcus; Goals; Gram-Positive Bacteria; Growth; Histology; IL8 gene; Immune; Incidence; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interferons; Interleukin-6; Interleukin-8; Interphase Cell; Lead; Lipopolysaccharides; Measures; Modeling; Monocyte Chemoattractant Protein-1; Natural Immunity; Neutrophil Activation; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Peptidoglycan; Peroxidases; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Postoperative Period; Process; Production; Recovery; Retina; Retinal; Safety; Signal Transduction; Site; Staphylococcus aureus; Stat3 protein; Steroids; Structure of retinal pigment epithelium; System; Therapeutic; Tight Junctions; Time; Toll-like receptors; Trauma; Up-Regulation; Vancomycin; Vascular Endothelial Growth Factors; Virulence; Virulent; Vision; Visual; base; cell type; chemokine; cytokine; diabetic rat; inflammatory marker; inhibitor/antagonist; migration; neovascular; neutrophil; novel; pathogen; prevent; public health relevance; receptor; research study; response; sensor; small molecule; src Homology Region 2 Domain; standard of care; stem; transcription factor

DESCRIPTION (provided by applicant): The objective of this proposal is to examine the efficacy of CLT-005 in reducing ocular inflammation and that occurs during endophthalmitis. Endophthalmitis occurs following the introduction of foreign pathogens into the eye. In addition to pathogenic virulence, the infiltration of immune cells into the eye is a major factor is contributing to loss of vision. These infiltrating immune cells can extremely adverse effects of the retina and RPE, which lead to cellular loss, resulting in detrimental affects on vision. The current standard of care of endophthalmitis is to treat with antibiotics, preferably administered by means of an intravitreal injection. These antibiotics perform well in destroying foreign virulent factors, but fail to prevent ocular inflammation, which can be as damaging to vision as the pathogen itself. To address inflammation, the administration of a steroid, such as dexamethasone, is often given concurrently with antibiotics; however, multiple studies have demonstrated that dexamethasone does not exert any beneficial effect on reducing inflammation and visual outcome. Therefore, a strong need exists to develop new anti-inflammatory therapies to be used in conjunction with antibiotics to prevent visual loss as a consequence of ocular inflammation. As Stat3 is a major effector molecule that is involved in the initial production of pro-inflammatory molecule that attract immune cells to infiltrate into the eye, we hypothesize that inhibition of Stat3 can prevent this upstream signaling that leads to rampant immune cell infiltration, and subsequent destruction of ocular cells. We have developed a small molecule (CLT-005) that inhibits dimerization of Stat3 and prevents Stat3-induced changes in gene expression. CLT-005 is potent, cell permeable, and well tolerated following intravitreal injection. In our preliminary data, we have shown that CLT-005: 1) is predicted to bind to the SH2 domain of Stat3, thus blocking dimerization and activation of this transcription factor; and 2) reduces the expression of pro-inflammatory genes ICAM-1, MCP- 1, and TNF-1 as well as pro-angiogenic genes such as VEGF, LRP-5, and LRP6 in a rat model of diabetes. Based on these promising data, we propose to evaluate the effect of CLT-005 in reducing ocular inflammation stemming from endophthalmitis. In this Phase I proposal, we will intravitreally administer various doses of CLT-005 alone or in conjunction with an antibiotic, Zymar, to a rabbit model of endophthalmitis induced by Staphylococcus aureus. We will assess bacterial proliferation, immune cell infiltration, histology, breakdown of the blood retinal barrier, and vision (as measured by ERG) at multiple time points following treatment. We will also perform these experiments in a rabbit model of endophthalmitis induced by metabolically-inactive Staphylococcus aureus, to examine the pure anti-inflammatory effect of CLT-005 in the absence of replicating pathogens. If this Phase I project demonstrates a benefit for the use of CLT-005 in the clinical management of endophthalmitis, these experiments will justify Phase II studies to further define efficacy and safety profiles that are requisite prior to the filing of an investigative new drug application with the FDA. PUBLIC HEALTH RELEVANCE: Endophthalmitis is a condition caused by the introduction of foreign material and pathogens into the eye. Vision loss occurs in response to both pathogen replication and immune cell infiltration into the eye. The current standard of care is to treat patients with local antibiotics and steroids, but many studies have demonstrated that steroids do not provide any benefit, and may even be detrimental. The goal of this proposal is to establish anti-inflammatory efficacy for CLT-005, a small molecule therapeutic that inhibits initial inflammatory signaling, to be used as an adjuvant therapy to antibiotics in the clinical management of endophthalmitis.

描述（由申请人提供）：该提案的目的是检查 CLT-005 在减少眼部炎症以及眼内炎期间发生的炎症方面的功效。外来病原体进入眼睛后会发生眼内炎。除了致病毒力外，免疫细胞浸润到眼睛也是导致视力丧失的一个主要因素。这些浸润的免疫细胞会对视网膜和视网膜色素上皮产生极其不利的影响，导致细胞损失，从而对视力产生不利影响。目前眼内炎的护理标准是用抗生素治疗，优选通过玻璃体内注射的方式施用。这些抗生素在消灭外来有毒因子方面表现良好，但无法预防眼部炎症，眼部炎症与病原体本身一样对视力造成损害。为了解决炎症，通常会与抗生素同时使用类固醇（例如地塞米松）。然而，多项研究表明，地塞米松对减轻炎症和视力结果没有任何有益作用。因此，迫切需要开发新的抗炎疗法，与抗生素联合使用，以防止眼部炎症导致的视力丧失。由于 Stat3 是一种主要效应分子，参与促炎分子的初始产生，吸引免疫细胞浸润到眼睛中，因此我们假设抑制 Stat3 可以阻止这种导致免疫细胞大量浸润的上游信号传导，以及随后的免疫细胞浸润。眼细胞的破坏。我们开发了一种小分子 (CLT-005)，可以抑制 Stat3 二聚化并防止 Stat3 诱导的基因表达变化。 CLT-005 有效，具有细胞渗透性，玻璃体内注射后耐受性良好。在我们的初步数据中，我们已经表明 CLT-005：1) 预计会与 Stat3 的 SH2 结构域结合，从而阻断该转录因子的二聚化和激活； 2)降低糖尿病大鼠模型中促炎基因ICAM-1、MCP-1和TNF-1以及促血管生成基因例如VEGF、LRP-5和LRP6的表达。基于这些有希望的数据，我们建议评估 CLT-005 在减少眼内炎引起的眼部炎症方面的效果。在此一期提案中，我们将单独或与抗生素 Zymar 联合使用不同剂量的 CLT-005 玻璃体内注射至由金黄色葡萄球菌诱导的兔眼内炎模型。我们将在治疗后的多个时间点评估细菌增殖、免疫细胞浸润、组织学、血视网膜屏障的破坏和视力（通过 ERG 测量）。我们还将在由代谢失活的金黄色葡萄球菌诱导的兔眼内炎模型中进行这些实验，以检查 CLT-005 在没有复制病原体的情况下的纯抗炎作用。如果该 I 期项目证明使用 CLT-005 在眼内炎临床管理中具有益处，那么这些实验将证明 II 期研究的合理性，以进一步确定在提交研究性新药申请之前所需的功效和安全性概况。 FDA。公共卫生相关性：眼内炎是一种因异物和病原体进入眼睛而引起的疾病。视力丧失是由于病原体复制和免疫细胞渗入眼睛而发生的。目前的护理标准是用局部抗生素和类固醇治疗患者，但许多研究表明类固醇没有任何益处，甚至可能有害。该提案的目标是确定 CLT-005 的抗炎功效，CLT-005 是一种抑制初始炎症信号传导的小分子治疗药物，可在眼内炎的临床治疗中用作抗生素的辅助治疗。