Therapy for ocular mustard gas exposure using engineered FGF derivatives

E And B Technologies, Llc, San Diego CA

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Abstract

? DESCRIPTION (provided by applicant): Mustard gas (sulfur mustard, SM) and related vesicants have been used as weapons of war and are considered by the US government to be a potential terrorist threat to the civilian population. These agents cause rapid, significant and debilitating injuries to the skin, lungs and eyes. The eye and particularly the cornea is the tissu most sensitive to exposure. SM exposure drives microvesication with Deepithelialization of the corneal surface and results in significant pain and degradation of vision. No effective treatment for vesicant injury is known. Treatments that could reduce the corneal lesions and accelerate healing of the corneal surface would be highly valuable subsequent to an attack. The goal of this research is to produce effective therapeutics for SM corneal injury by using engineered versions of naturally occurring growth factors. These substances, including many members of the fibroblast growth factor (FGF) family, are part of the natural wound healing response and can accelerate the healing of a wide variety of corneal wounds. The efficacy of both endogenously produced and exogenously applied growth factors in the context of SM injury may be limited by the sensitivity of growth factors to inactivation by SM, degradation by proteases induced following injury and/or by diffusion of the growth factors from the surface of the eye and the wound bed. We have produced engineered versions of FGF-1, a key growth factor involved in the healing process, that should overcome many of the limitations of the endogenous protein and facilitate its use as an ocular therapy for mustard gas exposure. This research project will first test engineered FGF-1 (eFGF-1) molecules for efficacy in the rabbit corneal organ culture model to prove the hypothesis that the eFGF-1s can accelerate healing of vesicant injury. Two eFGF-1 molecules that 1) lack any of the free thiols of native FGF-1; 2) have additional stability enhancing mutations including an internal disulfide bond; and 3) do not require heparin co-factors will be evaluated. These derivatives should not be modified by any residual SM, be considerably less susceptible to proteolysis and should be retained in the wound site through interactions with sulfated proteoglycans of the extracellular matrix. The ability of these molecules to accelerate the regeneration and proliferation of the ocular surface and inhibit the expression of wound related markers will be shown. Finally, the ability of the eFGF-1s to accelerate healing in the rabbit eye following SM exposure in vivo will be demonstrated. If this work is successful, these eFGF-1s will be advanced into clinical development for SM injury.