Title: Targeting STAT3 for the management of diabetic retinopathy
Funder: Juvenile Diabetes Research Foundation

Abstract: Diabetic retinopathy (DR) affects nearly 80% individuals who have had diabetes for 1-2 decades, and after 30 years duration of diabetes, the presence of DR is almost universal. Patients with DR may lose vision due to diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR). Around 30% of type 1 diabetes (T1D) patients may develop DME and ~40% may suffer from PDR after 25-year duration of diabetes. Current therapies including focal- or pan-retinal photocoagulation and intravitreal injection of steroid are not satisfactory. Although the recent use of anti-vascular endothelial growth factor (VEGF) intravitreal injections provide better visual outcomes, only about 50% of patients with DME respond to the therapy. Furthermore, there are serious concerns about the long-term adverse effects since VEGF is an essential survival factor to many retinal cells. New safe and effective therapies are urgently needed. The Signal Transducers and Activators of Transcription (STAT) proteins are key molecules involved in cytokine JDRF Strategic Research Agreement (SRA) - Targeting STAT3 for the management of diabetic retinopathy Target Discovery and Validation for Diabetic Retinopathy RFA - 2014 page 8 of 16receptor-mediated signal transduction and gene transcription. The STAT3 protein is activated by IL-6-family cytokines, IL-10, and GM-CSF. Activation of STAT3 is often related to angiogenesis, inflammation and cell proliferation. Previous studies have shown that the activated form of STAT3 (pSTAT3) is present in the diabetic retina in animal models, and we have now shown this to be the case in human diabetic retina. Also in our preliminary studies, we have found that STAT3 is also activated in blood cells from a murine model of T1D. More importantly, we have found that inhibition of STAT3 can suppress pathogenic retinal angiogenesis in a murine model of PDR. Therefore we propose that STAT3 may be a novel therapeutic target for DR. In this proof-of-concept study, we will: 1) verify whether targeting STAT3 can prevent or ameliorate DR pathologies in pre-clinical models of DR, and 2) examine whether STAT3 is activated in T1D patients with early stages of DR and PDR. Using oxygen-induced retinopathy (OIR) in mice as a commonly used model for PDR, we will test whether a STAT3-specific inhibitor (LLL12) can prevent or suppress pathogenic angiogenesis and improve retinal function. The effect of STAT3 inhibition on early-stage DR, as exemplified by leukostasis, blood retina barrier (BRB) breakdown, vascular degeneration (acellular capillary formation) and neural degeneration will be tested in a murine model of T1D (Ins2Akita mice). The STAT3 inhibitor will be administered intraperitoneally or intravitreally to test whether therapeutic efficacy can be achieved through systemic or local delivery. To verify if the STAT3 pathway is involved in human DR, we will carry out immunohistochemistry investigations in human eyes with/without DR to examine the relationship between retinal pathology and STAT3 activation (phosphorylation of STAT3). We will also examine whether STAT3 is activated in blood cells isolated from T1D patients and how these levels are related to the severity of DR. A number of STAT3 inhibitors have been developed in the cancer field and at least three products are in phase I/II clinical trials for the management of different cancers. If we prove that STAT3 inhibition is also beneficial to DR, it is highly likely that these drugs can readily be re-purposed for use in patients to prevent progression of DR to the sight-threatening end-points.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE;METABOLIC AND ENDOCRINE