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James T Rosenbaum, Bruce H. Littman, Frank W Marcoux, Jeffrey Adam Jamison; Efficacy of PPL-003 and Inhibition of NFκB Activation in a Rabbit Mycobacterial Antigen-Induced Uveitis Model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1896. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The efficacy of topical and intra-vitreal (IVT) PPL-003 was evaluated utilizing a mycobacterial antigen-induced rabbit model of uveitis. PPL-003 is a cell penetrating peptide (CPP) that includes a human-derived CPP sequence and a region able to reduce NFκB activation by blocking formation of the upstream IκB kinase complex. Since NFκB signaling is a central mechanism in chronic inflammatory diseases such as uveitis, PPL-003 may have corticosteroid-like efficacy without steroid-like adverse events.
Male NZW rabbits were immunized (IM) with mycobacterial antigen on Day -14 and uveitis was induced on Day -1 in all rabbits by IVT injection of mycobacterial antigen into the left eye only. Topical t.i.d. (50 μL) treatments in both eyes (PPL-003 or vehicle, N=5, and 0.05% difluprednate , N=2) began on Day 0 and 50 μL IVT PPL-003 injections in both eyes were administered on Day 0 and 6. PPL-003 concentrations were 1.66 mg/ml, 0.45 mg/ml and 0.03 mg/ml. Rabbits were sacrificed on Day 14. Treatment effects were assessed by measuring anterior chamber (AC) cells and vitreous haze (4 point scales) pre-dose and on Day 1, 4, 7, 10 and 13.
Topical PPL-003 (Figure 1) reduced AC cells but only the high concentration group reduced vitreous haze compared to vehicle. Difluprednate had the lowest topical treatment scores in both AC cells and vitreous haze. IVT PPL-003 treatments (Figure 2) had efficacy in the AC at all concentrations and in the vitreous at mid and high concentrations on Days 7 and 10. In this pilot study no treatment effects were statistically significant due to model variability and the small number of eyes per group. High concentration IVT treatment was associated with higher Day 13 vitreal haze scores in both eyes suggesting PPL-003 interaction with vitreal components.
PPL-003 topical treatment reduced AC cells at all concentrations and at the highest concentration also reduced vitreous haze supporting the hypothesis that this CPP therapeutic can penetrate into the eye and exhibit its anti-inflammatory activity. IVT PPL-003 treatment was active in both the AC and vitreous. This finding supports NFκB activation as a therapeutic target and the further development of PPL-003 for inflammatory eye disease.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Figure 1: Results of Topical Treatments
Figure 2: Results of IVT Treatments
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