title: Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy.
abstract: Diabetic retinopathy is a leading cause of vision loss. Previous studies have shown signaling pathways mediated by Stat3 (signal transducer and activator of transcription 3) play a primary role in diabetic retinopathy progression. This study tested CLT-005, a small molecule inhibitor of Stat3, for its dose-dependent therapeutic effects on vision loss in a rat model of diabetic retinopathy.
  
  
  
  Brown Norway rats were administered streptozotocin (STZ) to induce diabetes. CLT-005 was administered daily by oral gavage for 16 weeks at concentrations of 125, 250, or 500 mg/kg, respectively, beginning 4 days post streptozotocin administration. Systemic and ocular drug concentration was quantified with mass spectrometry. Visual function was monitored at 2-week intervals from 6 to 16 weeks using optokinetic tracking to measure visual acuity and contrast sensitivity. The presence and severity of cataracts was visually monitored and correlated to visual acuity. The transcription and translation of multiple angiogenic factors and inflammatory cytokines were measured by real-time polymerase chain reaction and Multiplex immunoassay.
  
  
  
  Streptozotocin-diabetic rats sustain progressive vision loss over 16 weeks, and this loss in visual function is rescued in a dose-dependent manner by CLT-005. This positive therapeutic effect correlates to the positive effects of CLT-005 on vascular leakage and the presence of inflammatory cytokines in the retina.
  
  
  
  The present study indicates that Stat3 inhibition has strong therapeutic potential for the treatment of vision loss in diabetic retinopathy.
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Vanlandingham
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Didier J
authors.initials: DJ
authors.lastname: Nuno
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Quiambao
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Phelps
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States 2EyeCRO, LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Wassel
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors.forename: Krysten M
authors.initials: KM
authors.lastname: Farjo
authors.affiliation: Charlesson LLC, Oklahoma City, Oklahoma, United States 2EyeCRO, LLC, Oklahoma City, Oklahoma, United States.
authors.forename: Rafal A
authors.initials: RA
authors.lastname: Farjo
mesh_terms: D000818:Animals; D001766:Blindness / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D015151:Immunoblotting; D050828:Protein Inhibitors of Activated STAT / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014792:Visual Acuity
chemical_list: D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat