Novel Treatment for Post-LASIK Ectasia

LASIK 术后扩张的新型治疗方法

• 批准号: 7747113
• 负责人: Matthew S Mattson
• 金额: $ 34.8万
• 依托单位: VISDEX CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747113
• 关键词: Aftercare; Animals; Anterior; Apoptosis; Attenuated; Beds; Biological Assay; Blindness; Cells; Clinical Trials; Collaborations; Complication; Computer Simulation; Cornea; Corneal Stroma; Defect; Devices; Diffuse; Diffusion; Disadvantaged; Disease Progression; Drops; Drug Formulations; Edema; Endothelial Cells; Endothelium; Eosine Yellowish; Event; Excision; Exposure to; Eye; FDA approved; Family suidae; Gel; Gold; Human; In Situ; In Vitro; Investigation; Keratoconus; Keratoplasty; Laser In Situ Keratomileusis; Lasers; Lead; Lifting; Light; Measures; Mechanics; Methods; Modeling; Operative Surgical Procedures; Oryctolagus cuniculus; Pain; Pathological Dilatation; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiologic Intraocular Pressure; Porifera; Positioning Attribute; Probability; Procedures; Protocols documentation; Residual state; Retinal; Riboflavin; Risk; Safety; Shapes; Small Business Technology Transfer Research; Solutions; Source; Staging; Sterility; Stratification; Surface; Surgeon; Surgical Flaps; System; Testing; Therapeutic; Thick; Time; Tissues; Topical application; Toxic effect; Toxicity Tests; Translating; Ultraviolet Rays; United States; Visible Radiation; Visual; biomaterial compatibility; clinical application; corneal epithelium; cost; crosslink; cytotoxic; design; high risk; in vitro testing; in vivo; innovation; irradiation; keratomileusis; killings; light intensity; light treatment; macula; novel; prevent; prophylactic; public health relevance; research study; time interval; tool

DESCRIPTION (provided by applicant): Of the 1.4 million refractive surgeries performed each year using laser assisted in situ keratomileusis (LASIK) in the U.S., 1 in 2500 will result in post-LASIK ectasia-a thinning and bulging of the cornea analogous to keratoconus that becomes evident months or years after the LASIK procedure. Studies of patients who developed post-LASIK ectasia have led to a risk stratification system that uses preoperative information to evaluate the risk of developing post-LASIK ectasia. Approximately 1/3 of patients satisfy the conditions that correlate with developing post-LASIK ectasia. If a treatment were available with sufficiently low cost, low risk and high efficacy, patients in the "at risk" group might be treated prophylactically to greatly reduce the probability of subsequent ectasia. Some cases of post-LASIK ectasia occur in patients who have preoperative profiles that would not be identified as "at risk;" therefore, a safe and effective means to arrest the progression of ectasia as soon as it is identified is also needed. Corneal crosslinking using the riboflavin/UVA protocol pioneered by Wollensak, Seiler, and Spoerl, has shown promise in halting the progress of post-LASIK ectasia, providing a potential treatment to postpone or avoid corneal transpantation necessitated by the ectasia. However, the treatment is costly (requiring a surgeon to perform the 35 minute procedure), painful (requiring that the cornea be debrided) and toxic (the treatment kills all cells in the anterior 300 <m of the cornea; in the event that the cornea has already thinned to <400 <m, the treatment can permanently damage the endothelium). A proprietary treatment developed through collaboration of Visdex, Caltech, and UCSF successfully stabilizes corneal shape in vitro using visible light to activate Eosin Y. In relation to application as a prophylactic or a treatment for post-LASIK ectasia, the treatment would consist of lifting the LASIK flap, applying a drop of a drug to the surface of the stromal bed, closing the LASIK flap, allowing the drug to diffuse into the tissue (ca. 10 min) and then irradiating the cornea with visible light for 5 min. The treatment uses compounds that have been approved by the FDA for use in patients. Initial in-vivo experiments in rabbits indicate that the drug and irradiation are well tolerated by the eye. The objective of this Phase I STTR project is to demonstrate that such a treatment can be translated into a clinically meaningful protocol that shows efficacy in vitro matching that of the riboflavin/UVA treatment and shows safety in vivo, in contrast to the apoptosis and edema caused by riboflavin/UVA. First, in vitro experiments will optimize the Eosin Y formulation and delivery vehicles for administration under a LASIK flap, and will optimize the light delivery device to reduce treatment time and minimize retinal light exposure (Aim 1). Second, efficacy will be evaluated in vitro, testing and further optimizing the Eosin Y formulation and annular irradiation device to stabilize corneal shape after creating LASIK flaps in enucleated animal eyes (Aim 2). Finally, safety and efficacy will be evaluated in vivo using a rabbit model with the optimized Eosin Y formulation and irradiation device developed in Aims #1 and #2. By demonstrating in-vitro efficacy and in-vivo biocompatibility, this Phase I project will advance the innovative visible light activated treatment toward clinical application. Specifically, this study would set the stage for a Phase II study that would evaluate mechanical stability in human donor eyes and extend toxicity tests needed before human clinical trials. PUBLIC HEALTH RELEVANCE: Post-laser in situ keratomileusis (LASIK) ectasia is a serious complication of refractive corneal procedures resulting in progressive steepening and thinning of the cornea that can lead to severe visual loss and require corneal transplantation. This project will result in an innovative light-activated treatment that will arrest post-LASIK ectasia for those who already developed it and will serve as a preventative measure for others who are receiving the refractive correction procedure.

描述（由申请人提供）：在美国每年进行的140万次屈光手术中，在美国的现场角膜瘤（LASIK）中，2500分之1将导致Lasia-a ectasia-a变薄，并使角膜类似于lasik ectifter of lassik processure persecture。对开发Lasik eCtasia的患者的研究导致了风险分层系统，该系统使用术前信息来评估发展后lasik ectasia的风险。大约1/3的患者满足与发展后lasik ectasia相关的疾病。如果可以接受足够低成本，低风险和高疗效的治疗，则可以对“处于危险”组的患者进行预防治疗，以极大地降低随后的鼻症的可能性。在术前患者中发生了某些术后lasik ectasia的病例，这些患者的术前特征不被确定为“有风险”；因此，还需要一旦确定，一种安全有效的手段来阻止欧克西亚的进展。使用Wollensak，Seiler和Spoerl率先使用的核黄素/UVA方案进行角膜交联在停止Lasik ectasia的进展方面有希望，从而提供了潜在的治疗方法，可以推迟或避免Ectasia需要的角膜转移。但是，治疗是昂贵的（需要外科医生执行35分钟的手术），疼痛（要求将角膜清除）和有毒（治疗杀死了角膜前300 <m的所有细胞；如果角膜已经稀薄到<400 <m，则治疗可能会永久损害内皮内膜）。通过Visdex，Caltech和UCSF的合作而开发的专有治疗扩散到组织中（大约10分钟），然后用可见光辐射角膜5分钟。该治疗使用FDA批准的化合物用于患者。兔子中的初始体内实验表明，眼睛可以很好地耐受药物和辐射。该阶段ISTTR项目的目的是证明可以将这种治疗转化为一种临床意义的方案，该方案在体外匹配核黄素/UVA治疗方面有效，并显示了体内的安全性，与核黄素/UVA引起的凋亡和凋亡性和水肿相反。首先，体外实验将优化在LASIK襟翼下用于给药的曙红配方和输送车辆，并将优化光递送装置以减少治疗时间并最大程度地减少视网膜光线的暴露（AIM 1）。其次，将在体外评估疗效，测试并进一步优化曙红的配方和环形照射装置，以稳定角膜形状，以在浓缩的动物眼中产生lasik襟翼（AIM 2）。最后，将使用兔模型在AIMS＃1和2中开发出优化的曙红配方和辐照装置的兔模型对安全性和功效进行评估。通过证明体外功效和体内生物相容性，该阶段I项目将推动创新的可见光光激活治疗方法朝着临床应用。具体而言，这项研究将为II期研究奠定了阶段，该研究将评估人类供体眼中的机械稳定性，并扩展人类临床试验之前所需的毒性测试。公共卫生相关性：射击后原位角膜肌（Lasik）eCtasia是折射角膜手术的严重并发症，导致角膜逐渐陡峭和稀疏，可导致严重的视觉损失并需要角膜移植。该项目将导致一种创新的光激活治疗方法，该治疗将为那些已经开发出它的人而逮捕Lasik ectasia，并将作为接受屈光矫正程序的其他人的预防措施。