Therapy for ocular mustard gas exposure using engineered FGF derivatives

使用工程 FGF 衍生物治疗眼部芥子气暴露

• 批准号: 9564274
• 负责人: David D Eveleth
• 金额: $ 7万
• 依托单位: E AND B TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564274
• 关键词: Acute; Alkylation; Beds; Binding; Bioterrorism; Cells; Cornea; Corneal Injury; Data; Development; Diffusion; Dose; Effectiveness; Engineering; Epithelial Cell Proliferation; Event; Exposure to; Extracellular Matrix; Eye; Eye Injuries; Eyedrops; FGF1 gene; Family; Fibroblast Growth Factor; Fluorescein; Foundations; Functional disorder; Gelatinase B; Goals; Government; Growth Factor; Heparin; In Vitro; Individual; Injury; Lesion; Lung; Magnetic Resonance Imaging; Measures; Mechlorethamine; Modeling; Monitor; Mustard; Mustard Gas; Mutation; Natural regeneration; Organ; Organ Culture Techniques; Oryctolagus cuniculus; Pain; Peptide Hydrolases; Phase; Population; Positioning Attribute; Process; Property; Proteins; Proteoglycan; Proteolysis; Research; Research Project Grants; Residual state; Resistance; Severities; Site; Skin; Staining method; Stains; Stromal Cells; Sulfhydryl Compounds; Surface; System; TNF-alpha converting enzyme; Testing; Time; Tissues; Treatment Efficacy; Unspecified or Sulfate Ion Sulfates; Vesicants; Vision; Visual; War; Work; Wound Healing; analog; clinical development; disulfide bond; effective therapy; experimental study; healing; improved; in vivo; injured; member; migration; neovascularization; ocular surface; programs; public health relevance; response; vapor; weapons; wound

 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.

 描述（由适用提供）：芥末天然气（Sulphur Mustard，SM）和相关的囊泡药已被用作战争武器，并被美国政府视为对平民的潜在恐怖威胁。这些药物对皮肤，肺和眼睛造成快速，显着和使人衰弱的伤害。眼睛，尤其是角膜是对暴露最敏感的组织。 SM暴露会通过角膜表面进行深层化驱动微化，并导致明显的疼痛和视力降解。尚无有效的囊泡损伤治疗方法。在攻击之后，可能会减少角膜损伤并加速角膜表面的愈合的治疗方法将是高度有价值的。这项研究的目的是通过使用天然发生的生长因子的工程版本来产生有效的SM角膜损伤疗法。这些物质，包括成纤维细胞生长因子（FGF）家族的许多成员，是自然伤口愈合反应的一部分，可以加速各种角膜伤口的愈合。在SM损伤的背景下，内源性产生和明确应用生长因子的效率可能受到生长因子对SM失活的敏感性的限制，受伤后蛋白质降解和/或通过从眼表和伤口床的表面扩散而诱导的蛋白质降解。我们生产了FGF-1的工程版本，FGF-1是康复过程中涉及的关键生长因子，该版本应该克服内源性蛋白质的许多局限性，并促进其用作芥末气体暴露的眼部疗法。该研究项目将首先测试兔角膜器官培养模型的FGF-1（EFGF-1）分子的效率，以证明EFGF-1可以加速囊泡损伤的愈合。两个EFGF-1分子，1）缺乏天然FGF-1的任何游离硫醇； 2）具有额外的稳定性增强突变，包括内部二硫键； 3）不需要评估肝素的辅助因子。这些衍生物不应通过任何残留的SM来修饰，不太容易受到蛋白水解的影响，并且应通过与细胞外基质的硫酸化蛋白聚糖相互作用将其保留在伤口部位。这些分子能够加速眼表加速和增殖并抑制与伤口相关标记的表达的能力。最后，将证明EFGF-1在体内SM暴露后加速兔眼愈合的能力。如果这项工作成功，这些EFGF-1将进入SM损伤的临床发展。