Investigating the pathogenetic mechanisms leading to progressive scarring and glaucoma surgery failure and development of new targeted therapeutics

青光眼是一个主要的健康问题，全世界有数百万人因此失明。青光眼手术是用来预防失明的，但在5年的随访后，50%的患者会留下疤痕，因此手术失败。詹姆斯·林德联盟和视力丧失和视力优先设定伙伴关系将青光眼研究的首要任务列为发现高风险的青光眼患者以迅速进展和改善青光眼的治疗方法。我将使用新的强大的技术来调查为什么一大批患者在青光眼手术后会出现严重的疤痕和不可逆的视力丧失。利用这些知识，我将开发新的治疗方法来防止这种情况的发生。主要目标：1)前瞻性研究300例首次青光眼手术后18个月内的详细情况，以确定导致瘢痕形成的复杂因素，寻找预测瘢痕形成和手术失败高风险的标志物。本研究将利用尖端的眼组织技术和对患者的详细眼科检查来研究青光眼手术后瘢痕形成的复杂因素。该项目将直接改善青光眼患者的管理，识别出更容易手术失败和需要额外治疗的高危患者，以防止手术失败。2)针对导致瘢痕形成的关键因素，开发新的治疗方法，防止青光眼手术失败。目前的黄金标准是丝裂霉素-c，它是一种非特异性毒性抗癌药物，具有致盲的副作用。因此，对具有更强靶向性和更低毒性的新药的临床需求尚未得到满足。我将开发新的靶向药物来抑制青光眼手术后导致瘢痕形成的关键因素。我还会用青光眼手术的兔子模型来测试最有效的靶向药物。这些研究将为未来青光眼靶向药物的临床试验提供信息。该项目的最终目标是开发和转化一种新的抗疤痕药物，以提高青光眼手术的成功率，而不使患者暴露于有毒抗癌药物的风险中。我将建立产业合作伙伴关系，针对导致瘢痕形成的关键因素，并为青光眼患者翻译新的靶向药物。我还将与Rayne研究所（伦敦国王学院）的良好生产规范（GMP）机构合作，开发一种安全一致的方法来生产新的靶向药物，这些药物可以在未来的青光眼患者中进行临床试验。优势：该奖学金具有创新性，汇集了多个学科和领域的专业知识（临床医生，分子遗传学和靶向药物的学术领袖，药物开发的关键工业合作伙伴，基因治疗的GMP设施合作伙伴）。该项目将通过识别那些更有可能手术失败的患者，并通过开发新的针对性和个性化治疗方法，直接改善青光眼患者的管理。

Glaucoma is a major health problem and blinds millions of people worldwide. Glaucoma surgery is used to prevent blindness, but it fails primarily due to scarring in 50% of patients after 5 years of follow-up. The James Lind Alliance and the Sight Loss and Vision Priority Setting Partnership list among the top priorities for glaucoma research the detection of glaucoma patients with a higher risk to progress rapidly and the improvement of treatments for glaucoma. I will use new powerful technologies to investigate why a large subgroup of patients develops severe scarring and irreversible loss of vision after glaucoma surgery. Using this knowledge, I will develop new treatments to prevent this from happening.KEY GOALS:1) To prospectively study 300 patients after their first glaucoma surgery in detail over 18 months to identify the complex factors that cause scarring, and to look for markers that predict a high risk of scarring and surgical failure.This research will use cutting-edge techniques on eye tissues and detailed eye examination from patients to study the complex factors associated with scarring after glaucoma surgery. This project will directly improve the management of glaucoma patients by identifying the high-risk patients who are more likely to fail surgery and who need additional treatment to prevent surgical failure.2) To develop new treatments to target the key factors that cause scarring and to prevent glaucoma surgery from failing.The current gold standard, mitomycin-C, is a non-specific toxic anti-cancer drug with blinding side effects. There is thus a large unmet clinical need for new drugs with more targeted effects and less toxicity. I will develop new targeted drugs to silence the key factors that lead to scarring after glaucoma surgery. I will also test the most effective targeted drugs using a rabbit model of glaucoma surgery. These studies will help to inform future clinical trials of targeted drugs in glaucoma.This project's ultimate aim is to develop and translate a new anti-scarring drug to increase the success rate of glaucoma surgery, without exposing patients to the risk of toxic anti-cancer drugs. I will form industrial partnerships to target the key factors that cause scarring and for the translation of new targeted drugs in glaucoma patients. I will also work with the Good Manufacturing Practice (GMP) facility at the Rayne Institute (King's College London) to develop a safe and consistent method to manufacture the new targeted drugs, which can be tested in glaucoma patients in future clinical trials.BENEFITS:This Fellowship is innovative and brings together the expertise of multiple academic disciplines and fields (clinical doctors, academic leaders in molecular genetics and targeted drugs, key industrial partner in drug development, GMP facility partner in gene therapy). This project will directly improve the management of glaucoma patients by identifying those who are more likely to fail surgery, and by developing new targeted and personalised treatments.