Diabetic retinopathy (DR) is the leading cause of blindness and visual impairment in US adults. The currentstandard of care for DR is intravitreal (IVT) injection of anti-vascular endothelial growth factor (VEGF)therapeutics to inhibit vascular permeability and neovascularization. However, anti-VEGF drugs have limitedefficacy in a substantial percentage of DR patients. The invasiveness of IVT injections also correlates with poorcompliance as well as serious side effects. As such, there is an unmet medical need for an innovativenoninvasive treatment that effectively mitigates DR pathogenesis and progression. In this research application,we propose to evaluate the therapeutic potential of a peptide-containing eye drop formulation (iNexinâ¢) tomitigate DR pathophysiology by preserving blood-retina barrier (BRB) integrity. The BRB, which is formed bytight junctions of retinal vascular endothelial cells and retinal pigment epithelial cells, breaks down early in DRpathogenesis and causes vascular permeability and leakage as well as inflammation, leading to loss of retinalhomeostasis and neurodegeneration. Diabetes-associated factors also disrupt gap junction intercellularcommunications to further exacerbate DR. Therefore, protecting intercellular junctions represents a significanttherapeutic opportunity to treat DR. Connexin43 (Cx43) is a transmembrane protein component of intercellularjunctions that is instrumental to barrier function integrity, cell-cell communication, and apoptosis. FirstStringResearch Inc. has developed a therapeutic peptide mimetic of Cx43, alpha-Connexin Carboxy-Terminal (aCT1),that stabilizes intercellular junctions while tempering hemichannel activity to preserve barrier function, reduceinjury spread, and decrease inflammation. iNexin is a stable non-steroidal, preservative-free aCT1 eye dropformulation validated in a comprehensive set of safety and efficacy studies. From these studies, we hypothesizethat iNexin treatment will stabilize intercellular junctions comprising the BRB to ameliorate DR pathophysiology,preserving retinal health and function. To test this hypothesis, we propose to demonstrate proof-of-conceptefficacy of iNexin to mitigate diabetic retinopathy (Aim 1), and to confirm aCT1 biodistribution in the diabetic eyefollowing eye drop administration (Aim 2). Using a translationally relevant streptozotocin-induced type 1 diabeticrat model, we propose to evaluate the impact of iNexin on DR using two distinct treatment paradigms. The firstinitiates iNexin administration concurrent with the onset of hyperglycemia; the second initiates treatment at theclinical manifestation of retinal vascular abnormalities. We will also confirm aCT1 biodistribution in the diabeticeye following topical ocular administration and aCT1's localization to retinal epithelial and endothelial cells.Successful completion of these activities will provide proof-of-concept efficacy for aCT1's mechanism of actiontranslating to therapeutic effectiveness in the treatment of DR, while also supporting project advancement intoefficacy and safety studies in large (non-rodent) animal models of DR. Translation into the clinic will meansignificantly improved outcomes for the >8M diabetic adults in the US alone.
Public Health Relevance Statement: Project Narrative
Diabetic retinopathy (DR) is the leading cause of vision loss and blindness in working-age adults worldwide.
Current standard of care treatments for DR have limited effectiveness for many patients while also requiring
invasive intravitreal injections that result in poor compliance and serious side effects. Here we propose to
evaluate the potential of an innovative peptide-containing eye drop formulation as a noninvasive treatment for
DR using a translationally relevant Type 1 diabetic animal model.
Project Terms: <21+ years old>|
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