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

描述（由申请人提供）：本申请的目的是研究CLT-005在减轻眼内炎期间发生的眼部炎症方面的疗效。眼内炎发生在外来病原体进入眼睛后。除了致病性外，免疫细胞渗入眼睛是导致视力丧失的一个主要因素。这些浸润性免疫细胞会对视网膜和RPE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。目前治疗眼内炎的标准是用抗生素治疗，最好是通过玻璃体内注射。这些抗生素在消灭外来致病因子方面表现良好，但不能预防眼部炎症，而眼部炎症对视力的损害与病原体本身一样大。为了治疗炎症，类固醇药物，如地塞米松，通常与抗生素同时使用；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，以防止因眼部炎症而导致的视力丧失。由于Stat3是一种主要的效应分子，参与了促炎分子的初始产生，吸引免疫细胞浸润到眼睛中，我们假设抑制Stat3可以阻止这种上游信号传导，导致免疫细胞的猖獗浸润，并随后破坏眼细胞。我们已经开发了一种小分子（CLT-005），可以抑制Stat3的二聚化，并阻止Stat3诱导的基因表达变化。CLT-005在玻璃体内注射后具有强效、细胞渗透性和良好的耐受性。在我们的初步数据中，我们已经表明CLT-005: 1)被预测与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、TNF-1以及促血管生成基因VEGF、LRP-5、LRP6的表达。基于这些有希望的数据，我们建议评估CLT-005在减轻眼内炎引起的眼部炎症中的作用。在这个I期计划中，我们将通过玻璃体内给药不同剂量的CLT-005单独或联合抗生素Zymar，治疗由金黄色葡萄球菌引起的兔眼内炎模型。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、血液视网膜屏障的破坏和视力（通过ERG测量）。我们还将在代谢无活性金黄色葡萄球菌引起的兔眼内炎模型中进行这些实验，以检验在没有复制病原体的情况下CLT-005的纯抗炎作用。如果这个I期项目证明了CLT-005在眼内炎临床治疗中的益处，这些实验将证明II期研究的合理性，以进一步确定在向FDA提交调查性新药申请之前所必需的有效性和安全性。公共卫生相关性：眼内炎是由异物和病原体进入眼睛引起的一种疾病。视力丧失是对病原体复制和免疫细胞渗入眼睛的反应。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，甚至可能是有害的。CLT-005是一种抑制初始炎症信号的小分子治疗药物，本研究的目的是建立CLT-005的抗炎疗效，在眼内炎的临床治疗中作为抗生素的辅助治疗。

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.