Therapeutic Corneal Cross-Linking Using Formaldehyde Releasing Agents

 描述（由申请人提供）：尽管使用戊二醛和甲醛固定组织是许多过程和程序（即组织学处理等）的主要方法，与过去和现在的医学实践相关，用于治疗人类疾病的“在患者体内”诱导组织交联[治疗性组织交联（TXL）]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（LASIK=激光辅助原位角膜磨镶术）中的全球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。尽管它很好，但CXL也有局限性，特别是需要对角膜上皮进行清创（疼痛、感染风险、愈合延迟、混浊）和使用紫外线（UV） 光线（对透镜和视网膜有潜在的损害，甚至有致癌风险）。 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治疗方法，并了解酶交联如何促进疾病的发展，特别是在KC中。该特定申请的总体目标是开发一种用于角膜变薄疾病的新治疗，其将用作开发其他疾病（例如近视中的巩膜等）中的类似治疗的“跳板”。甲醛释放剂（法尔斯）是一组有前途的化合物，被化妆品工业广泛用作个人护理产品（PCP）中的化学防腐剂。这些法尔斯可用于替代目的，即作为治疗性组织交联剂。将实现以下目标：1.使用评价细胞毒性和组织固定的离体角膜交联模拟装置，建立使用法尔斯进行治疗性角膜组织交联的最佳条件。2.为了检验局部应用法尔斯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和法尔斯）。 预期这些目标将产生：1）用于诱导组织交联作为KC的疗法的安全且有效的方法，其保持上皮完整且不需要使用UV光。2)更深入地了解酶交联在圆锥角膜发病机制中的作用，以及开发新的治疗性交联反应的生物标志物。具有使用局部交联剂交联角膜的能力将“打开大门”，以将该方法应用于治疗机械组织失效起作用的其他疾病，包括进行性近视中的巩膜。

 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.