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

研究导致进行性疤痕和青光眼手术失败的发病机制并开发新的靶向治疗方法

• 批准号: MR/T027932/1
• 负责人: Cynthia Yu-Wai-Man
• 金额: $ 152.46万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT027932%2F1
• 关键词: Investigating; pathogenetic; mechanisms; leading; progressive

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.

青光眼是一个主要的健康问题，全世界有数百万人失明。青光眼手术用于预防失明，但在5年随访后，50%的患者主要由于疤痕而失败。James Lind联盟和视力丧失和视力优先设置伙伴关系列出了青光眼研究的首要任务，即检测具有更高风险的青光眼患者，以快速进展和改善青光眼治疗。我将使用新的强大的技术来调查为什么一个大的亚组的患者发展严重的疤痕和不可逆转的视力丧失后青光眼手术。主要目标：1）对300例首次青光眼手术后的患者进行前瞻性研究，详细分析18个月内导致瘢痕形成的复杂因素，并寻找预测瘢痕形成和手术失败高风险的标志物。本研究将使用最先进的眼组织技术和对患者进行详细的眼部检查，研究与青光眼手术后瘢痕形成相关的复杂因素。该项目将通过识别更有可能手术失败的高危患者和需要额外治疗以防止手术失败的患者，直接改善青光眼患者的管理。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。目前的金标准丝裂霉素C是一种具有致盲副作用的非特异性毒性抗癌药物。因此，对于具有更靶向作用和更低毒性的新药存在大量未满足的临床需求。我将开发新的靶向药物，以沉默导致青光眼手术后瘢痕形成的关键因素。我还将使用青光眼手术的兔子模型来测试最有效的靶向药物。这些研究将有助于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瘢痕形成药物，以提高青光眼手术的成功率，而不会使患者暴露于有毒抗癌药物的风险中。我将建立工业伙伴关系，以针对导致疤痕的关键因素，并为青光眼患者翻译新的靶向药物。我还将与Rayne研究所（伦敦伦敦）的药品生产质量管理规范（GMP）设施合作，开发一种安全、一致的方法来生产新的靶向药物，该药物可以在未来的临床试验中在青光眼患者中进行测试。好处：该奖学金是创新的，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导者，药物开发的主要工业合作伙伴，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，并通过开发新的有针对性的个性化治疗方法，直接改善青光眼患者的管理。

项目成果

Peripapillary and optic nerve head vessel density of glaucoma and healthy subjects from Afro-Caribbean and European descent: A pilot study.

• DOI: 10.1016/j.jfo.2021.07.010
• 发表时间: 2021-12
• 期刊: Journal francais d'ophtalmologie
• 作者: L. Salazar-Quiñones;C. Yu-Wai-Man;A. de Antonio Ramirez;C. Mendez-Hernandez;A. Daas;J. García Feijóo

Non-Viral Gene Therapy in Trabecular Meshwork Cells to Prevent Fibrosis in Minimally Invasive Glaucoma Surgery.

• DOI: 10.3390/pharmaceutics14112472
• 发表时间: 2022-11-16
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Luo J;Tan G;Thong KX;Kafetzis KN;Vallabh N;Sheridan CM;Sato Y;Harashima H;Tagalakis AD;Yu-Wai-Man C
• 通讯作者: Yu-Wai-Man C

Anterior segment OCT (AS-OCT) bleb imaging after Trabeculectomy and PreserFloTM MicroShunt: a prospective, multicentre, masked, quantitative interobserver analysis on bleb scarring.

小梁切除术和 PreserFloTM MicroShunt 后的眼前节 OCT (AS-OCT) 滤泡成像：对滤泡疤痕的前瞻性、多中心、隐蔽、定量观察者间分析。

• 发表时间: 2023
• 期刊: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
• 影响因子: 4.4
• 作者: Fajardo-Sanchez Julia

Long-term outcomes in Primary congenital glaucoma, aniridia and anterior segment dysgenesis.

• DOI: 10.1177/11206721211073208
• 发表时间: 2022-09
• 期刊: EUROPEAN JOURNAL OF OPHTHALMOLOGY
• 影响因子: 1.7
• 作者: Magan, Tejal;Tanner, Alexander;Fajardo-Sanchez, Julia;Lim, Kin Sheng;Goyal, Saurabh;Rodrigues, Ian;Amaya, Luis;Trikha, Sameer;Kulkarni, Avinash;Hammond, Christopher;Lascaratos, Gerassimos;Yu-Wai-Man, Cynthia
• 通讯作者: Yu-Wai-Man, Cynthia

Building a UK Glaucoma Bioresource: a disease-specific biobank for advancing translational research in glaucoma

建立英国青光眼生物资源：用于推进青光眼转化研究的疾病特异性生物库

• 发表时间: 2023
• 期刊: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
• 影响因子: 4.4
• 作者: Magan Tejal