The Use of Photobiomodulation (PBM) in the Treatment for Diabetic Macular Edema

摘要 糖尿病影响全球超过2.84亿人，20%的糖尿病患者发生糖尿病黄斑病变 水肿（DME）是一种严重的眼部并发症，会损害视觉功能，如果 不治疗。对于DME患者，目前的治疗包括激光光凝手术和玻璃体内注射。 抗VEGF注射，这是侵入性和昂贵的程序。光生物调节（PBM）疗法 包括暴露于对靶组织的低水平光辐射， 线粒体输出和临床结果的改善。干性年龄相关性黄斑变性（AMD） 与DME具有相同的病理学特征，包括线粒体功能障碍和炎症， 严重的视力丧失在干性AMD中进行了几项试点研究，例如，TORPA I & II，LIGHTSITE I，显示了 PBM治疗后视觉和解剖学终点的改善。最近一 LIGHTSITE I研究，视力和对比敏感度在临床上和统计学上显著改善， 观察到玻璃疣厚度和玻璃疣体积减少，日常生活活动改善 PBM治疗后立即进行。使用多个预先选择的波长施用PBM治疗， 使用Valeda®光递送系统刺激线粒体功能并抑制VEGF表达。 Valeda是唯一获得商业批准（CE认证）的干性AMD治疗设备。 目前的SBIR提案旨在将Valeda治疗的实用性扩展到DME人群， 使用LumiThera的Valeda光输送系统进行前瞻性、双盲临床试验， 两个顶级视网膜DME中心：斯坦福大学（PI：Diana Do和Quan Nguyen博士）和纽约眼耳中心 医务室（NYEE，PI：Richard罗森博士）。两个中心都有使用Valeda器械的经验，研究 具体目标将确定多波长的临床、解剖学和代谢受益的程度 将40例DME患者分为两组。约20例受试者将接受PBM治疗， 20名受试者将使用Valeda光递送系统接受每周3次假治疗，持续3周。 斯坦福大学和NYEE提供了顶级的DME研究环境，以进行这种创新，探索 临床试验将对所有受试者进行临床（视力和对比敏感度）和解剖学评估。 (OCT和OCT-A成像）在基线和治疗后1、3和6个月（M）的结果。代谢 将在每次PBM治疗后以及M3和M6时测量结果（黄素蛋白荧光）， 确定线粒体改善的时间进程和长期效应持续时间。 这些发现将为一项关键性试验提供基本的安全性和科学基础， DME的侵入性非药物治疗。

ABSTRACT Diabetes affects over 284 million people worldwide and 20% of diabetic patients develop diabetic macular edema (DME), a significant ocular complication that impairs visual function, eventually leading to blindness if left untreated. For patients with DME, current treatment involves laser photocoagulation surgery and intravitreal anti-VEGF injections, which are invasive and expensive procedures. Photobiomodulation (PBM) therapy consists of exposure to low levels of light radiation to targeted tissues resulting in beneficial effects to mitochondrial output and improvements in clinical outcomes. Dry age-related macular degeneration (AMD) shares overlapping pathology with DME including mitochondrial dysfunction and inflammation leading to significant vision loss. Several pilot studies in Dry AMD, e.g., TORPA I & II, LIGHTSITE I, have shown improvements in both visual and anatomical endpoints following PBM treatment. In the most recent LIGHTSITE I study, clinically and statistically significant improvement in visual acuity and contrast sensitivity, reductions in drusen thickness and drusen volume, and improvements in activities of daily living were observed immediately after PBM treatment. PBM treatment was administered using multiple pre-selected wavelengths to stimulate mitochondrial function and to suppress VEGF expression with the Valeda® Light Delivery System. Valeda is the only commercially approved device (CE mark) for dry AMD treatment. The current SBIR proposal aims to expand the utility of the Valeda treatment into the DME population and conduct a pilot prospective, double-masked clinical trial with LumiThera’s Valeda Light Delivery System, with two top retinal DME centers: Stanford (PI: Drs. Diana Do and Quan Nguyen) and the New York Eye and Ear Infirmary (NYEE, PI: Dr. Richard Rosen). Both centers have experience with the Valeda device, and the Study Specific Aims will establish the magnitude of clinical, anatomical and metabolic benefit of multi-wavelength PBM on 40 DME patients, divided into two groups. Approximately 20 subjects will receive PBM treatment and 20 subjects will receive sham treatment 3x per week for 3 weeks using the Valeda Light Delivery System. Stanford University and NYEE provide top DME research environments to conduct this innovative, exploratory clinical trial. All subjects will be assessed for clinical (visual acuity and contrast sensitivity) and anatomical (OCT and OCT-A imaging) outcomes at baseline and Months (M) 1, 3 and 6 post-treatment. Metabolic outcomes (flavoprotein fluorescence) will be measured after each PBM treatment as well as at M3 and M6 to establish the time course of mitochondrial improvement and long-term duration of effect. The findings will provide the basic safety and scientific foundation for a pivotal trial with a novel non- invasive, non-pharmaceutical therapy for DME.