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: 9106336
• 负责人: DAVID C PAIK
• 金额: $ 41.89万
• 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/9106336
• 关键词: 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; Health; Histologic; Impaired wound healing; In Situ; Industry; Infection; Keratoconus; Laser In Situ Keratomileusis; Lasers; Lead; Life; Mechanics; Medical; Methods; Myopia; Natural regeneration; Outcome; Pain; Pathogenesis; Patient Care; Patients; Permeability; Photochemistry; Play; Procedures; Process; Progressive Myopia; Property; Protein-Lysine 6-Oxidase; Proteins; Reaction; Retina; Riboflavin; Risk; Role; Safety; Sclera; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Technology; Testing; Therapeutic; 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; novel; personal care products; rapid growth; research clinical testing; simulation; standard of care; therapeutic biomarker; 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)：尽管使用戊二醛和甲醛固定组织一直是许多过程和程序(如组织学处理等)的支柱。在过去和现在的医疗实践中，在患者体内诱导组织交联剂[治疗组织交联剂(TXL)]用于治疗人类疾病是新的。治疗圆锥角膜(KC)和准分子激光原位角膜磨镶术(LASIK)后的角膜扩张症(LASIK)的核黄素光化学疗法(CXL)在全球范围内迅速发展，证明了体内组织交联化是可能的，从患者护理的角度来看也是有益的。尽管CXL是好的，但它也有局限性，特别是需要清创角膜上皮(疼痛、感染风险、延迟愈合、雾霾)和使用紫外线(UV)。 光(对晶状体和视网膜有潜在损害，甚至有患癌症的风险)。我们的长期目标是通过使用体内治疗组织交联剂来开发人类疾病的治疗方法，并了解酶交联剂如何促进疾病的发展，特别是在KC中。这一特殊应用的总体目标是开发一种针对角膜变薄疾病的NW疗法，将作为开发其他疾病(如近视的巩膜等)的类似疗法的“跳板”。甲醛释放剂(FARS)是一类很有前途的化合物，广泛应用于化妆品行业作为个人护理产品的化学防腐剂。这些FAR可用于另一目的，即作为治疗组织交联剂。1.利用建立的评价细胞毒性和组织固定的体外角膜交联剂模拟实验，建立FARS治疗性角膜组织交联剂的最佳条件。2.验证局部应用FARS可以安全有效地诱导活体眼角膜交联化的假说。3.利用化学分析方法(LC/MS和MALDI-TOF)对圆锥角膜中酶促胶原交联物进行定量，并确定诱导交联物(CXL和FARS)的生物标志物。预计这些目标将产生：1)一种安全有效的诱导组织交联化的方法，作为治疗KC的方法，使上皮保持完整，不需要使用紫外线。2)加深对酶促交联剂在圆锥角膜发病机制中作用的认识，为治疗性交联剂的研究开发新的生物标志物。拥有使用局部交联剂使角膜交联化的能力，将为将这种方法应用于其他机械组织衰竭起作用的疾病的治疗打开大门，包括进行性近视的巩膜。