This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D.

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1 1 MONDAY 28 days in vivo in recipient sheep after orthotopic corneal allotransplantation of a transduced donor cornea. However, the kinetics of LV-mediated gene expression were slower than those achieved by comparable adenoviral vectors. Further, 24 hour transduction of ovine corneal endothelium with LV-IL10 resulted in mRNA levels that were logarithmically lower than those achieved by an adenoviral vector. Shortening the transduction period to 2 hours led to a further reduction in gene expression. The addition of 40 ;g/ml polybrene to the transduction mixture restored expression to levels comparable to those attained after a 24 hour transduction period, but at the cost of associated toxicity for corneal epithelium. Allografts transduced for 2-3 hours with LV-SV40-IL10 in the absence of polybrene were rejected at a median of 25 days (n=7) compared with 18 days in the combined sham-treated and LV-SV40-eYFP control group (n=14) (p=0.026). Vectors containing the PGK or EF promoter were not more effective than LV-SV40-eYFP in driving transgene expression in ovine corneas, but LV-CMV-eYFP generated signifi cantly better, faster expression at low multiplicity of infection. Interestingly, LV-mediated eYFP and IL10 expression was signifi cantly higher and more rapid in organ-cultured human corneas (the eventual target species of interest) than in ovine corneas. Conclusions: Ovine and human corneal endothelial cells were effi ciently transduced by the lentiviral vector. LV-SV40-IL10 prolonged ovine corneal allograft survival to a modest, albeit signifi cant extent. Species differences were apparent in LV-mediated transduction effi ciency, but promoter exchange signifi cantly improved transgene expression levels. Aims: Our aims were to examine graft survival and visual outcome after corneal transplantation and to identify risk factors for graft failure within a large, prospective national register. Methods: Records of 17,090 full-thickness (penetrating) corneal grafts were examined within a prospectively-maintained, national database, with annual archival follow-up extending from one to 22 years. Information was available on the recipient, donor, eye bank practice, surgical procedure, and on postoperative outcomes. Kaplan-Meier survival analysis was used to indicate variables of interest for Cox proportional hazards regression analysis. A model clustered by individual patient to control for inter-eye or inter-graft dependence was constructed to identify variables best predicting penetrating corneal graft failure. Visual acuity in the grafted eye was measured by best-corrected Snellen acuity (without pinhole). Results: The major indications for corneal transplantation were keratoconus (32%). bullous keratopathy (26%). failed previous graft (19%). corneal dystrophy (7%). and herpetic eye disease (4%). Probability of corneal graft survival was 0.87 at one year, 0.73 at 5 years, 0.62 at 10 years and 0.51 at 15 years. Variables predicting graft failure in multivariate analysis included transplant centre, location and volume o...

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