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Vincent Ling, Arne Nystuen, Susan Elliott, Lisa Orecchio, Brenda Dean, Konrad Kauper, Weng Tao; Generation of Combination PDGF / VEGF-antagonist ECT devices. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3290.
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PDGF and VEGF are potent pro-angiogenic molecules implicated in neovascular diseases. Anti-VEGF therapies that inhibit blood vessel growth have been successfully used in the treatment of certain cases of wet AMD, but with only ~30% of treated patients gain 3 lines of vision. It is hypothesized that regression of CNV may be improved with the addition of anti-PDGF therapies that target the pericyte cellular scaffolding surrounding blood vessels. To that end, we generated PDGFR-Fc producing cell lines and ECT devices for the potential treatment of wet AMD. We also explored the concept of combination delivery of PDGFR-Fc and NT-503 VEGFR-Fc from an ECT device system.
PDGFR-Fc cell lines were produced by standard transfection into NTC-200 cells, followed by by screening for highest recombinant protein productivity via ELISA. These new NT-506 PDGFR-Fc cell lines and Neurotech NT-503 VEGFR-Fc cell lines were encapsulated by loading into 7.2 mm ECT devices either separately, or in combination as a 50% mixture of each cell line. Devices were implanted into rabbits for 1 month, after which device explants were assessed for secretion of PDGFR-Fc and VEGFR-Fc molecules.
Stable PDGFR-Fc cell lines were produced that secreted ~ 15 picogram per cell per day (pcd). PDGFR-Fc / PDGF binding was established by direct binding and solution-phase ELISA assays on purified PDGFR-Fc. Bioactivity of PDGFR-Fc was demonstrated by inhibition of PDGF-based cellular migration assays. In-vivo PDGFR-Fc ECT implants exhibited sustained production of PDGFR-Fc protein after one month, as based on explant device culture and vitreal PDGFR-Fc accumulation. Mixed-cell line ECT implants were also effective in the simultaneous production of PDGFR-Fc and VEGFR-Fc, proportional to initial cell loading.
Here we show the ability of ECT to sustain production of a PDGF antagonist which may have practical application in conjunction with anti-VEGF therapy. As an initial proof-of-concept, we show that a mixed-cell line ECT implant affords simultaneous delivery of PDGF / VEGF antagonists and may represent a potent future treatment modality for wet AMD.
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