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

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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.