Evaluation of a Connexin-based Peptide for the Treatment of Diabetic Retinopathy - Diabetic retinopathy (DR) is the leading cause of blindness and visual impairment in US adults. The current
standard 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 limited
efficacy in a substantial percentage of DR patients. The invasiveness of IVT injections also correlates with poor
compliance as well as serious side effects. As such, there is an unmet medical need for an innovative
noninvasive 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 (iNexin™) to
mitigate DR pathophysiology by preserving blood-retina barrier (BRB) integrity. The BRB, which is formed by
tight junctions of retinal vascular endothelial cells and retinal pigment epithelial cells, breaks down early in DR
pathogenesis and causes vascular permeability and leakage as well as inflammation, leading to loss of retinal
homeostasis and neurodegeneration. Diabetes-associated factors also disrupt gap junction intercellular
communications to further exacerbate DR. Therefore, protecting intercellular junctions represents a significant
therapeutic opportunity to treat DR. Connexin43 (Cx43) is a transmembrane protein component of intercellular
junctions that is instrumental to barrier function integrity, cell-cell communication, and apoptosis. FirstString
Research 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, reduce
injury spread, and decrease inflammation. iNexin is a stable non-steroidal, preservative-free aCT1 eye drop
formulation validated in a comprehensive set of safety and efficacy studies. From these studies, we hypothesize
that 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-concept
efficacy of iNexin to mitigate diabetic retinopathy (Aim 1), and to confirm aCT1 biodistribution in the diabetic eye
following eye drop administration (Aim 2). Using a translationally relevant streptozotocin-induced type 1 diabetic
rat model, we propose to evaluate the impact of iNexin on DR using two distinct treatment paradigms. The first
initiates iNexin administration concurrent with the onset of hyperglycemia; the second initiates treatment at the
clinical manifestation of retinal vascular abnormalities. We will also confirm aCT1 biodistribution in the diabetic
eye 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 action
translating to therapeutic effectiveness in the treatment of DR, while also supporting project advancement into
efficacy and safety studies in large (non-rodent) animal models of DR. Translation into the clinic will mean
significantly improved outcomes for the >8M diabetic adults in the US alone.
