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Scott Ellis, Kyriacos Mitrophanous, Maria A Parker, Vicky Scripps, Trevor J McFarland, Matthew Hartzell, Binoy Appukuttan, Tim Stout; NONCLINICAL DEVELOPMENT OF ENCORSTAT®, DONOR CORNEAL TISSUE GENETICALLY ENGINEERED TO PREVENT GRAFT REJECTION. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3235.
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Corneal transplantation is one of the most successful transplant procedures due to the relatively immune-privileged status of the eye. However there is a 14% failure rate in the first year and in high rejection risk patients (such as those with failed grafts) it is considerably higher (50-90%) due to vascularisation of the recipient corneal bed. The most common reason for graft failure in patients is irreversible immunological rejection so it is unsurprising that neovascularisation (both pre- and post-grafting) is a significant risk factor for subsequent graft failure. This is therefore a logical target to prevent corneal graft rejection. EncorStat® is human donor corneal tissue engineered by a novel process prior to transplant to prevent rejection by suppressing neovascularisation. This is achieved by the ex vivo delivery of the genes encoding secretable forms of the angiostatic human proteins, endostatin and angiostatin, using a non-replicating, recombinant lentiviral vector product derived from Equine Infectious Anaemia Virus (EIAV).
Parameters of the EncorStat® process were tested (incubation time, washing/shedding). Modified rabbit corneas were 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 generate corneas that 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. Interestingly, this suppression was significant for all three parameters only in the prevascularised model, which may highlight a limitation of the suture-driven model.
The nonclinical data presented supports the evaluation of EncorStat® corneas in a First-in-Man trial. With support from the UK Technology Strategy Board, this trial will be conducted in 2015, following completion of nonclinical safety studies and GMP vector manufacture this year.
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