Cross Sectional Cataract Study with the NASA Dynamic Lig

白内障是世界上最主要的致盲原因，目前只能通过手术切除来治疗。尽管手术在美国容易获得且安全进行，但在亚洲、非洲、中东和南美洲等世界许多不发达地区，手术并不容易获得，也不安全进行。因此，我们正在研究用内科(非手术)疗法治疗白内障的方法。 关于白内障病因的一个主要理论是，晶状体内的晶状体蛋白聚集在一起，形成高分子量的“聚集体”，散射光线，导致晶状体混浊。这可能是由于过大的外部压力或内部保护系统无法工作所致。我们正在研究一项新技术，该技术将帮助我们找出可能导致白内障的晶状体组织发生了什么，从而帮助我们找到治疗白内障的方法。它还将有助于确定新的潜在抗白内障药物是否对患者有效，因为它可以在早期检测到白内障的进展或消退。 这项技术基于动态光散射(DLS)，可以检测分子相互作用，包括活着的患者晶状体中发生的晶体蛋白蛋白质相互作用。这项技术根据活着的眼睛内这些颗粒的布朗运动来分类颗粒的大小、形状和相互作用。 首次在白内障动物模型上使用新的DLS探针，我们确实发现晶状体蛋白聚集是白内障最初发展的过程。这些研究表明，DLS有可能检测到白内障发生的最早变化，在这个阶段，理论上抗白内障治疗在逆转、延迟或预防白内障方面最有效。 在俄亥俄州克利夫兰NASA约翰·格伦中心的Ansari博士和Suh博士的合作下，我们开发了一种用于患者的新的微型临床版本，根据初步研究中患者的反馈对其进行了修改。我们成功地将DLS探头安装在角膜镜上，这是角膜外科医生用来标测角膜的临床设备，它有一个3-D瞄准系统，以提高重复性。 然后，我们对15名正常人志愿者(第一阶段)进行了初步研究，以测试该仪器用于量化晶状体变化的安全性、有效性和可重复性，发现该仪器具有良好的重复性。我们还得出了平均对数颗粒大小(从颗粒大小分布得出)，作为我们数据的首选参数。 在本项目的第二阶段，我们成功招募并研究了250名患者，进行了一项横断面研究，以确定体内人类晶状体因衰老而发生的临床变化(与年龄相关的变化)，以及在三种主要类型的白内障(核性、皮质性和PSC)中发现的分子变化。每个患者都接受了全面的眼科检查、白内障临床分级、白内障摄影(随后由阅读中心对照片进行分级)，最后使用临床DLS设备进行测试。在这项NEI-IRB批准的研究中，所有患者都表示完全知情同意。 我们发现，在正常老化的情况下，小蛋白群有缓慢但持续的丢失，并不断增加高分子量的晶状体蛋白。在白内障形成过程中，我们观察到首先是缓慢的减少，然后是低分子量蛋白质的丢失。同时，高分子量蛋白质的急剧增加，使得在白内障(如AREDS临床2.5期核性白内障)中，所有的晶状体蛋白质形成一个大的分子量基团，甚至在许多情况下形成一个单一的峰。在一些皮质和后囊下白内障中，即使在核保持透明和似乎不受影响的情况下，晶状体核也有明显的分子变化。 值得指出的是，此前，这些在体、无创的晶状体老化和白内障研究甚至是不可能的，因为我们无法在分子水平上检测和测量这些早期晶状体和白内障的变化。这项新技术为研究可能导致白内障或预防白内障的条件和药物提供了一种新的、敏感和精确的方法。 对数据的统计分析表明，DLS数据与临床和摄影镜头分级数据具有良好的相关性，证明了该系统在检测和测量白内障变化方面的有效性。数据也显示出良好的重复性(误差小于5%)。 这项研究表明，DLS方法可以客观地检测和测量晶状体混浊(白内障)的严重程度，使其不仅适用于野外研究，也适用于远程研究，如监测宇航员在外层空间的白内障。这项技术的发展将帮助我们进行未来各种类型的临床白内障研究，具有极高的敏感性和准确性。这项技术将帮助我们更好地了解白内障的根本原因，并帮助我们开发和测试延缓、逆转或预防白内障形成的新疗法，如国家眼科研究所最近开发的TempolH眼药水。

Cataracts are the foremost cause of blindness in the world and currently can be treated only by surgical removal. Surgery, although easily available and safely performed in the U.S., is not easily available nor safely performed in many undeveloped regions in the world like Asia, Africa, the Middle East and South America. Hence we are studying ways to treat cataract using medical (non surgical) treatment. One principal theory on the cause of cataracts is that the crystallin proteins inside the lens clump together to form high molecular weight "aggregates" that scatter light and cause clouding of the lens. This can be due to overwhelming external stresses or failure of internal protective systems to work. We are working on a new technology that will help us find out what happens to the lens tissues that may lead to cataracts, and therefore help us find a cure for cataracts. It will also help determine if new potential anti cataract drugs do work in patients, since it can detect progression or regression of the cataract early on. This technology is based on Dynamic Light Scattering or DLS, that can detect molecular interactions, including lens crystallin protein interactions that occur in the lens of a living patient. This technology sorts out particle size, shape and interactions based on the brownian movement of these particles inside the living eye. First using the new DLS probe on animal models of cataract, we indeed found lens protein aggregation as a cataract initially develops. These studies showed the DLS's potential to detect the earliest changes occurring in cataract, at the stage where anti cataract treatment would theoretically be most effective in reversing, delaying or preventing cataracts. In collaboration with Drs. Ansari and Suh of NASA's John Glenn Center in Cleveland, Ohio, we developed a new miniaturized clinical version of this device for use on patients, modifying it using feedback from our patients in a preliminary study. We mounted the DLS probe successfully on the Keratoscope, a clinical device used by cornea surgeons to map the cornea, which has a 3-D aiming system to enhance repeatability. We then conducted a pilot study on 15 normal human volunteers (Phase 1) to test the safety, usefulness and reproducibility of this instrument for quantitating lens changes, and found good reproducibility. We also derived the mean log particle size (derived from particle size distribution) to be used as the preferred parameter to use for our data. In the current Phase 2 of this project, we successfully recruited and studied 250 patients in a cross sectional study to determine the clinical changes in the human lens in vivo due to aging (age related changes), as well as molecular changes found in the three main types of cataracts (nuclear, cortical and PSC). Each patient underwent a complete comprehensive eye examination, cataract clinical grading, photography of the cataract (followed by grading of the photograph by a Reading Center), and finally testing with the Clinical DLS device. All patients in this NEI-IRB approved study gave their full informed consent. We found that with normal aging, there is a slow but continuous loss of the small protein group, and continuous increase high molecular weight lens proteins. During cataract formation, we observed first a slow decrease, followed by loss of the low molecular weight proteins. Concurrently, there was a dramatic increase in high molecular weight proteins, so that in a cataract (such as an AREDS Clinical Stage 2.5 nuclear cataract), all the lens proteins formed a large molecular weight grouop or even a single peak in many cases. In some cortical and posterior subcapsular cataracts, there are marked molecular changes in the lens nucleus even when the nucleus remains clear and does not seem to be affected. It worth pointing out that previously, these in vivo, non invasive lens aging and cataract studies were not even possible because we had no way to detect and measure these early lens and cataract changes in the molecular level. This new technology offers a new, sensitive and precise method to study conditions and medications that can either cause cataract or prevent cataract. Statistical analysis of the data showed excellent correlation between DLS data and Clinical and photographic Lens Grading data, demonstrating the validity of the system in detecting and measuring cataractous change. The data also showed good reproducibility (less than 5% error). This study shows that the DLS method can detect and measure the severity of clouding of the lens (cataract) objectively, making it useful in field as well as remote studies such as in monitoring astronauts for cataract in outer space. The development of this technique will help us conduct future clinical cataract studies of all sorts, with great sensitivity and accuracy. This technology will help us to better understand the underlying causes of cataracts and help us develop and test new treatments to delay, reverse or prevent cataract formation such as the National Eye Institute's Tempol H eye drops which was recently developed.