Inhibition of Apaf‐1 as a potential therapeutic strategy to improve corneal quality.

Purpose About 12 million people in the world live with visual impairment due to corneal diseases while there's a shortage of corneal tissue suitable for transplantation. One of the major causes of inappropriateness of corneas to be transplanted is to have a low endothelial cell density being apoptosis a key mechanism mediating cell loss. The protein Apaf‐1 is a key regulator of the mitochondrial apoptotic pathway. We have developed a family of Apaf‐1 inhibitors that have shown to be active in other apoptosis based‐pathologies. Methods We have established a corneal storage model.Corneas were preserved at 4°C for 7 days followed by a rewarming period that resembles the implant. At 4°C the endothelium was intact but not the tight junction (TJ) integrity. Throughout the rewarming, apoptosis was induced as indicated by caspase 3 activation, resulting in cell loss. Results The addition of Apaf‐1 inhibitors in the storage media reduces apoptosis activation. Caspase 3 activity was diminished; anti‐apoptotic genes were up‐regulated and pro‐apoptotic down‐regulated resulting in a reduced endothelium loss. Apaf‐1 inhibitors not only probed to be active during the rewarming period but also at 4°C: surprisingly, their presence inhibited the TJ breakdown. Integrity of TJ is known to be crucial to maintain cellular morphology and corneal transparency. Conclusion The results hereby presented demonstrate a dual role of Apaf‐1 inhibitors in preserving the cornea integrity by keeping TJ integrity and inhibiting apoptosis. The use of these inhibitors in the clinical setting could increase the availability and quality of tissue to be transplanted. Commercial interest [ABSTRACT FROM AUTHOR]