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Scott Ellis, Maria Parker, Vicky Kennedy, Laura McCloskey, Trevor McFarland, Matt Hartzell, Binoy Appukuttan, Tim Stout, Kyriacos Mitrophanous; EncorStat®: a human donor cornea genetically engineered to resist rejection in high risk patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2262.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal transplantation is one of the most successful transplant procedures because of the relatively immune-privileged status of the eye and the avascularity of the cornea. However in high risk patients, which account for >20% of the 100,000 transplants carried out each year, the rejection rate is very high (50-90%) due to vascularisation of the recipient corneal bed. The prognosis in these patients is poor; some are no longer considered for replacement transplant and are left blind. The main reason for graft failure is irreversible immunological rejection and it is therefore unsurprising that neovascularisation (both pre- and post-grafting) is a significant risk factor for subsequent graft failure. Neovascularisation thus is an attractive target to prevent graft rejection.<br /> <br /> EncorStat® is a human donor cornea modified prior to transplant by the ex vivo delivery of the genes encoding secretable forms of the angiostatic human proteins, endostatin and angiostatin, by a lentiviral vector which subsequently prevents rejection by suppressing neovascularisation.
Parameters of the EncorStat® process have been tested (transduction media, incubation time, washing/shedding). Modified rabbit corneas have been evaluated in two different models of corneal rejection, a highly aggressive model in which rejection is driven by the retention of thick graft sutures, and a less aggressive model in which rejection is driven by prevascularising the recipient corneal bed prior to surgery. In this latter model thin sutures are used to secure the graft that are removed 2 weeks following surgery, which is more analogous to the clinical setting.
The process to generate EncorStat® corneas has been optimized to secrete substantial and persistent levels of angiostatic proteins with very little shedding of residual vector. These corneas substantially suppress corneal neovascularization, opacity and subsequent rejection in two rabbit models of cornea graft rejection.
The non-clinical data to be presented supports the evaluation of EncorStat®corneas in a First-in-Man trial. With support from the UK Technology Strategy Board (now Innovate UK), this trial will be conducted in 2015, following completion of non-clinical safety studies and GMP vector manufacture this year. An outline of this clinical trial design will also be presented.
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