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Ralph Bradshaw, Michael Blaber, Amuthakannan Subramanian, David Ornitz, David Eveleth; Accelerated healing of corneal endothelial lesions induced by engineered FGF-1 derivatives. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1269. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Engineered versions of FGF-1 are known to be potent stimulators of dissociated corneal endothelial cell proliferation in vitro. These experiments tested the ability of eFGF-1s to accelerate the healing of corneal endothelial lesions in an organ culture model
Methods: The eFGF-1s TTHX1001 and TTHX1114 was generated via site-directed mutagenesis and the enhanced stability and potency evaluated via isothermal equilibrium denaturation and X-ray crystallography. Stimulation of FGF receptors was evaluated in BAF3 cells. Mitogenic potency was tested using NIH 3T3 and primary human corneal endothelial cell cultures. Healing of corneal endothelial lesions was evaluated in an organ culture system using trypan blue quantification of the lesion areas.
Results: Both TTHX1001 and TTHX1114 have enhanced thermodynamic stability relative to the wild type FGF-1 and stimulate FGF receptors at lower concentrations. Both potently stimulated the proliferation of human corneal endothelial cells in culture, with TTHX1114 approximately 100-fold more potent than wild type FGF-1. These eFGFs also accelerated the healing of lesions in the corneal endothelium of rabbit corneas in organ culture. The increased potency of TTHX1001 and TTHX1114 was not proportional to the degree of thermodynamic stabilization.
Conclusions: Engineered FGFs can potently accelerate the healing of corneal endothelial lesions making these agents potential therapeutics for corneal endothelial dystrophies.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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