June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Engineered FGF-1 derivatives as protective agents in nitrogen mustard induced corneal injury
Author Affiliations & Notes
  • David Eveleth
    Trefoil Therapeutics, San Diego, California, United States
  • Jennifer Eveleth
    Trefoil Therapeutics, San Diego, California, United States
  • Marion K Gordon
    Rutgers University, Piscataway, New Jersey, United States
  • Amuthakannan Subramaniam
    Trefoil Therapeutics, San Diego, California, United States
  • Rita A Hahn
    Rutgers University, Piscataway, New Jersey, United States
  • Kenneth Thomas
    Trefoil Therapeutics, San Diego, California, United States
  • Michael blaber
    Florida State University , Tallahassee, Florida, United States
  • Ralph Bradshaw
    Trefoil Therapeutics, San Diego, California, United States
  • Footnotes
    Commercial Relationships   David Eveleth, Trefoil Therapeutics Inc (E); Jennifer Eveleth, Trefoil Therapeutics (E); Marion Gordon, None; Amuthakannan Subramaniam, Trefoil Therapeutics (E); Rita Hahn, None; Kenneth Thomas, Trefoil Therapeutics (C); Michael blaber, Trefoil Therapeutics (F); Ralph Bradshaw, Trefoil Therapeutics (E)
  • Footnotes
    Support  NIH/NEI Grant EY026777
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1176. doi:
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    • Get Citation

      David Eveleth, Jennifer Eveleth, Marion K Gordon, Amuthakannan Subramaniam, Rita A Hahn, Kenneth Thomas, Michael blaber, Ralph Bradshaw; Engineered FGF-1 derivatives as protective agents in nitrogen mustard induced corneal injury. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1176.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Sulfur and nitrogen mustard (NM) are powerful vesicants that attack all elements of the cornea but their initial effects are primarily on the epithelial cell layer. They act by several mechanisms including the alkylation of cysteine residues in proteins and would be expected to inactivate native FGF-1. Reductions in FGF-1 and its mRNA are known to result from exposure to mustard agents and this loss may play a role in the slow healing of mustard-induced lesions in the cornea. These experiments test the hypothesis that an engineered form of FGF-1, TTHX1114, modified to eliminate the susceptibility of native FGF-1 to cysteine modification might accelerate the healing of corneal mustard lesions in an organ culture model.

Methods : TTHX1114 lacks free cysteine residues, with two of these residues repaced by Ser and Val and the third converted to a disulfide bond by the introduction of a A66C substitution. The enhanced stability and potency of the factor was evaluated via isothermal equilibrium denaturation and X-ray crystallography.[DE1] Healing[RB2] of corneal lesions generated by NM, followed by treatment with TTHX1114, was evaluated in a rabbit corneal organ culture system. Lesion severity was graded by histopathology. Proliferation of corneal tissue in vitro was evaluated by EdU incorporation. Markers of lesion evolution, including ADAM17 and clusterin, were measured by immunohistochemistry and ELISA.

Results : TTHX1114 reduced the severity and accelerated the re-epithelialization of corneal lesions generated by NM as assessed by histopathologic grading. NM-induced changes in the expression of ADAM17 at the lesion site were reduced by TTHX1114 treatment. The upregulation of clusterin expression by NM was reduced by TTHX treatment. In the epithelial layer, NM strongly suppresses proliferation and TTHX1114 increased the proportion of proliferating cells as judged by EdU incorporation.

Conclusions : TTHX1114 can reduce the severity and accelerate the healing of corneal lesions making it a potential therapeutic for mustard or vesicant injuries. These findings are consistent with the view that at least a portion of NM damage is caused by destroying native FGF-1, and supports a key role of this factor in maintaining normal corneal epithelization.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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