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Connexin43 (Cx43) the Inflammasome Pathway and treatment of Non Responsive Persistent Corneal Epithelial Defects (PED)

Colin R Green1,2, Brian Levy2

1Department of Ophthalmology, University of Auckland and New Zealand National Eye Centre, Auckland, New Zealand

2OcuNexus Therapeutics Inc., San Diego, California



Overexpression of Cx43, resulting in hemichannel (HC) pathology and release of ATP into the extracellular milieu creates a perpetual cycle of inflammation resulting in ischemia and microvascular dropout. An antisense oligonucleotide (AsOGN) was developed to inhibit overexpression of Cx43 an integral protein of the gap junction which is upregulated following chronic injury or disease. Eyes experiencing trauma such as chemical/thermal injury exhibiting severe inflammation, limbal ischemia with microvascular dropout and PED non responsive to standard of care (SOC), were treated compassionately following approval of regulatory bodies.



AsOGN was formulated within a thermoreversible gel to facilitate placement and delivery of the active drug. Numerous in vitro and in vivo studies were carried out to confirm the mechanism of action (MOA). Safety studies included both animal and human administration prior to filing an IND. The administration of the AsOGN prevents the formation of the open pathological hemichannel thus blocking the release of ATP, the activation of the inflammasome pathway and as a result shutting down the destructive cycle of inflammation.



Nine patients were treated under a compassionate use protocol for PED secondary to chemical or thermal injury with PED refractory to SOC which consisted of irrigation, steroids, antibiotics, amniotic membrane or bandage contact lens and ascorbic acid. Clinical evaluation of these eyes revealed significant anterior segment inflammation, limbal ischemia with complete loss of blood flow, denuded epithelium of the cornea and conjunctiva. Treated patients responded to one to 2 applications of AsOGN under a bandage contact lens in place for approximately 8 hours. All re-epithelialized following treatment and the majority regained vision varying from 20/20 to 20/100.



The mechanism of HC blocking and inhibiting the cycle of inflammation was clinically demonstrated in these patients with remarkable recovery following failure of SOC. Biomicroscopy revealed severe inflammation, limbal ischemia and no blood flow to epithelium. Single application of the AsOGN inhibited Cx43, prevented further development of open gap junction HC’s and restored microvasculature at the limbus promoting normal blood flow and regeneration of the epithelium with sustained visual recovery.

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