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Rafal Farjo, Phillip Vanlandingham, Alexander Quiambao, Jodi Green, Didier J Nuno, Fadee Mondalek, Drew Wassel; Oral delivery of CLT-005, a Stat3 inhibitor, prevents visual acuity decline in an animal model of type 1 diabetes. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2248.
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Activation of Stat3 in the posterior segment is associated with early events that lead to inflammation and neovascularization. We have previously demonstrated that topical delivery of CLT-005, a small molecule inhibitor of Stat3, achieved therapeutic levels in the posterior segment and was efficacious in multiple animal models of Wet AMD and Dry AMD. We sought to assess the efficacy, safety, and ocular distribution of CLT-005 following chronic oral administration over 14 weeks to streptozotocin (STZ) diabetic rats.
Type 1 diabetes was induced in Brown Norway rats by intraperioteneal administration of STZ to rats on Day 1. Following confirmation of elevated blood glucose on Day 4, rats were treated with daily gavage of vehicle or CLT-005 at 125, 250, and 500 mg/kg for 14 weeks. In a positive control group, an insulin pellet was subcutaneously administered. Optokinetic tracking (OKT) was performed at regular intervals to quantify spatial frequency threshold and contrast threshold.
A decline in spatial frequency threshold and contrast threshold was observed in STZ-diabetic rats beginning at 8-10 weeks following STZ induction, which progressively worsened through week 14. Oral CLT-005 protected against this decline in a dose-dependent manner, and the 500 mg/kg dose significantly rescued losses in spatial frequency threshold and contrast sensitivity at weeks 10, 12, and 14 (p<0.01, ANOVA). A similar rescue was observed in insulin-implanted animals. Incidence and grade of cataracts was also significantly reduced in the 125, 250, and 500 mg/kg treatment groups at week 14. The blood glucose levels in CLT-005 treated animals were notably lower than vehicle controls; however, they were still elevated as compared to naïve or insulin-treated STZ-diabetic rats. Oral administration of CLT-005 did not produce any gross pathological findings or changes in body weight during the entire study duration.
Oral delivery of CLT-005 has a profound effect to prevent loss of spatial frequency threshold and contrast sensitivity in the STZ-model of type 1 diabetes. Chronic delivery over 14 weeks was well tolerated with no observable adverse effects. These data support future clinical studies of CLT-005 to prevent and ameliorate inflammatory and neovascular insults that lead to decreased visual acuity in patients with Diabetic Retinopathy and other diabetic eye diseases.
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