Therapeutic Corneal Cross-Linking Using Formaldehyde Releasing Agents

使用甲醛释放剂进行治疗性角膜交联

• 批准号: 9233107
• 负责人: DAVID C PAIK
• 金额: $ 39.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233107
• 关键词: Alpha Cell; Biological Assay; Biological Markers; Cells; Chemicals; Collagen; Connective Tissue; Cornea; Cosmetics; Debridement; Development; Disease; Enzymes; Epithelial; Epithelium; Equilibrium; Excision; Exposure to; Eye; Eyedrops; Failure; Formaldehyde; Glutaral; Goals; Histologic; Impaired wound healing; In Situ; Industry; Infection; Keratoconus; Laser In Situ Keratomileusis; Lasers; Lead; Mechanics; Medical; Methods; Myopia; Natural regeneration; Outcome; Pain; Pathogenesis; Patient Care; Patients; Permeability; Photochemistry; Play; Procedures; Process; Progressive Myopia; Protein-Lysine 6-Oxidase; Proteins; Reaction; Retina; Riboflavin; Risk; Role; Safety; Sclera; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Technology; Testing; Therapeutic; Thinness; Time; Tissue Fixation; Tissues; Topical application; Toxic effect; Ultraviolet Rays; Work; base; cancer risk; chemical group; corneal epithelium; crosslink; diagnostic biomarker; human disease; improved; in vivo; keratomileusis; lens; liquid chromatography mass spectrometry; mechanical properties; novel; personal care products; pre-clinical; public health relevance; rapid growth; research clinical testing; simulation; standard of care; therapy development

 DESCRIPTION (provided by applicant): Although fixation of tissues using glutaraldehyde and formaldehyde have been a mainstay of numerous processes and procedures (i.e. histologic processing, etc.) related to medical practice in the past and present, inducing tissue cross-linking "in the patient" [Therapeutic Tissue Cross-linking (TXL)], for treating human disease, is novel. The rapid growth throughout the world of CXL (riboflavin photochemistry) in treating keratoconus (KC) and post-LASIK keratectasias (LASIK=Laser-Assisted in situ Keratomileusis) is proving that in vivo tissue cross-linking is possible and can be beneficial from a patient care standpoint. As good as it is, CXL has limitations, especially the need for debridement of the corneal epithelium (painful, infection risk, delayed healing, haze) and the use of ultraviolet (UV) light (with potential damage to the lens and retina, and even cancer risk). Our long-term goal is to develop therapies for human diseases through the use of in vivo therapeutic tissue cross-linking and to understand how enzymatic cross-linking contributes to the development of disease, specifically in KC. The overall objective of this particular application is to develop a nw treatment for corneal thinning diseases that will serve as a "springboard" for the development of similar treatments in other diseases (such as sclera in myopia, etc.). Formaldehyde releasing agents (FARs) are a promising group of chemical compounds, used widespread by the cosmetics industry as chemical preservatives in personal care products (PCPs). These FARs can be used for an alternative purpose, namely as therapeutic tissue cross-linking agents. The following aims will be pursued: 1. Using an ex vivo corneal cross-linking simulation set up that evaluates both cell toxicity and tissue fixation, establish optimal conditions for therapeutic corneal tissue cross-linking using FARs. 2. To test the hypothesis that topically applied FARs can induce corneal cross-linking in a safe and effective manner in the living eye. 3. To utilize analytical chemical methods (LC/MS and MALDI-TOF) to quantitate enzymatic collagen cross-links in keratoconus corneas and identify biomarkers of the induced cross-linking reactions (CXL and FARs). It is anticipated that these aims will yield: 1) A safe and effective method for inducing tissue cross- linking as a therapy for KC that leaves the epithelium intact and does not require use of UV light. 2) A deeper understanding of the role of enzymatic cross-linking in the pathogenesis of keratoconus as well as the development of new biomarkers for the therapeutic cross-linking reactions. Having the ability to cross-link the cornea using a topical cross-linking agent will "open the door" to applying this method to the treatment of other diseases in which mechanical tissue failure plays a role, including the sclera in progressive myopia.

 描述（由申请人提供）：虽然过去和现在使用戊二醛和甲醛固定组织一直是与医疗实践相关的众多工艺和程序（即组织学处理等）的支柱，但在“患者体内”诱导组织交联[治疗性组织交联（TXL）]用于治疗人类疾病是新颖的。 CXL（核黄素光化学）在治疗圆锥角膜 (KC) 和 LASIK 术后角膜扩张症（LASIK=激光辅助原位角膜磨镶术）方面的快速增长证明了体内组织交联是可能的，并且从患者护理的角度来看是有益的。尽管 CXL 很好，但它也有局限性，尤其是需要清创角膜上皮（疼痛、感染风险、延迟愈合、浑浊）和使用紫外线 (UV) 光（对晶状体和视网膜有潜在损害，甚至有癌症风险）。 我们的长期目标是通过使用体内治疗性组织交联来开发人类疾病的疗法，并了解酶交联如何促进疾病的发展，特别是在 KC 中。这一特定应用的总体目标是开发一种针对角膜变薄疾病的新疗法，该疗法将作为开发其他疾病（例如近视巩膜等）的类似疗法的“跳板”。甲醛释放剂 (FAR) 是一类很有前景的化合物，在化妆品行业中广泛用作个人护理产品 (PCP) 中的化学防腐剂。这些 FAR 可用于其他目的，即作为治疗性组织交联剂。我们将追求以下目标： 1. 使用体外角膜交联模拟装置来评估细胞毒性和组织固定，为使用 FAR 进行治疗性角膜组织交联建立最佳条件。 2. 检验局部应用 FAR 可以在活体眼睛中以安全有效的方式诱导角膜交联的假设。 3. 利用分析化学方法（LC/MS 和 MALDI-TOF）定量圆锥角膜中的酶促胶原交联，并鉴定诱导交联反应的生物标志物（CXL 和 FAR）。 预计这些目标将产生： 1) 一种安全有效的诱导组织交联的方法作为 KC 的治疗方法，使上皮保持完整并且不需要使用紫外线。 2）更深入地了解酶交联在圆锥角膜发病机制中的作用以及开发用于治疗性交联反应的新生物标志物。具有使用局部交联剂交联角膜的能力将为将该方法应用于治疗机械组织衰竭起作用的其他疾病（包括进行性近视中的巩膜）“打开大门”。