Studies of Retinopathy of AIDS in the HAART Era

HAART时代艾滋病视网膜病变研究

• 批准号: 8244502
• 负责人: William R. Freeman
• 金额: $ 67.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-12-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244502
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Activities of Daily Living; Adverse effects; Affect; Antiviral Agents; Apoptosis; Apoptotic; Area; Automobile Driving; Autopsy; BAX gene; Blindness; Blood capillaries; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cavia; Cell Count; Central Nervous System Diseases; Charge; Cidofovir; Ciliary Body; Clinical; Clinical Trials; Collaborations; Cytomegalovirus; Cytomegalovirus Retinitis; Data; Development; Disease; Dose; Drops; Drug Delivery Systems; Drug Kinetics; Electrophysiology (science); Esters; Evaluation; Eye; Functional disorder; Future; Ganglion Cell Layer; Gene Chips; Grant; HIV; HIV Infections; HIV Seropositivity; Highly Active Antiretroviral Therapy; Histologic; Human; Immune; In Vitro; Individual; Infarction; Inflammatory; Injection of therapeutic agent; Lead; Lesion; Libraries; Lipids; Location; Masks; Measures; Messenger RNA; Methods; Minority; Modeling; Molecular; Molecular Genetics; Nature; Nerve Degeneration; Nerve Fibers; Neurologic; Nucleosides; Optic Nerve; Organic Anion Transporters; Particle Size; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Perimetry; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Prevalence; Primates; Quality of life; RANTES; Recovery; Research; Resistance; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Retinitis; Series; Severities; Site; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Thick; Time; Tissues; Toxic effect; Toxicokinetics; Toxicology; Virus; Vision; Visual; analog; antiretroviral therapy; base; capillary; cohort; cotton wool spots; cytokine; drug candidate; efficacy testing; illness length; in vivo; indexing; intravitreal injection; neurobehavioral; neuropsychological; novel; phosphonate; retina blood vessel structure; retinal damage; retinal nerve fiber layer; simulation; uptake

ABSTRACT In the current era of potent antiretroviral therapy, patients with HIV are well known to develop both infectious (typically Cytomegalovirus Retinitis) as well as non-infectious (retinal microvascular occlusions most often seen as cotton wool spots) forms of retinopathy. There are over one million HIV positive individuals in the US and the disease disproportionately affects minorities. At the present time, non-infectious retinopathy is common and we have shown it is a cause of vision loss even in eyes without overt infectious retinitis. There is structural damage to the inner retina in HIV patients and that this correlates with vision loss and dysfunction. Infectious CMV retinitis is still a cause of severe vision loss due to resistant CMV retinitis in patients who are not responding well or who cannot reliably take HAART therapy. We will use novel methods to analyze retinal structure and function in HIV patients. We will use molecular genetic methods to determine the molecular pathogenesis of retinopathy and plan to use a novel drug delivery system to develop intravitreal therapies for or difficult to treat CMV retinitis. First, we will determine the prevalence and severity of visual dysfunction in HIV patients. We hypothesize that the cumulative effect of these lesions and other areas of retinal vessel damage seen in HIV patients cause widespread retinal damage accounting for the vision loss. We will determine the correlates between retinal structure and function and real world vision performance such as quality of life and driving simulation. Retinal damage will be assessed using novel eye tracking spectral domain OCT technology and microperimetric techniques. Multifocal electrophysiology will determine the level of the retina most involved. For our second aim, autopsy eye mRNA will be analyzed to determine which pathogenic pathways are active in damaged areas. In addition, histologic and morphometric methods will be used to determine the amount of retinal ganglion cell and nerve fiber layer damage and it's correlation with activated pathogenic pathways. Optic nerve degeneration and apoptosis in tissue will also be evaluated. The third aim is to develop an ultra long acting drug delivery system for treatment of resistant CMV retinitis. We have determined that certain derivatives of cidofovir and antiviral acyclic nucleoside phosphonates are highly active against HCMV in vitro even in cases of virus resistant to the usually used anti-CMV compounds. We will be using a novel lipid derivitization method to crystallize these drugs to allow prolonged release and dissolution in the eye. Toxicity and pharmacokinetics will be optimized and be tested in models of retinitis as a precursor to future clinical trials.

抽象的 在当前有效的抗逆转录病毒疗法的时代，众所周知，HIV患者同时发展 感染性（通常是巨细胞病毒视网膜炎）以及非感染（视网膜微血管 闭塞最常被视为视网膜病的形式。有超过一百万 美国的艾滋病毒阳性人群和疾病对少数群体影响不成比例。在 当前的时间，非感染性视网膜病很常见，我们证明这是视力丧失的原因 即使在没有明显感染性视网膜炎的眼睛中。艾滋病毒中的内部视网膜有结构性损害 患者，这与视力丧失和功能障碍有关。感染性CMV视网膜炎仍然是 由于反应不佳​​或 谁无法可靠地接受HAART治疗。我们将使用新颖的方法来分析视网膜结构和 HIV患者的功能。我们将使用分子遗传学方法来确定分子 视网膜病的发病机理并计划使用新型药物输送系统发展玻璃体内 治疗或难以治疗CMV视网膜炎的疗法。首先，我们将确定的患病率和严重性 HIV患者的视觉功能障碍。我们假设这些病变和 艾滋病毒患者看到的其他视网膜血管损害的其他区域造成广泛的视网膜损害 考虑视力损失。我们将确定视网膜结构与功能之间的相关性 以及现实世界愿景的表现，例如生活质量和驱动模拟。视网膜损害将 使用新颖的眼睛跟踪光谱域OCT技术和微量尺度评估 技术。多灶性电生理学将确定最涉及的视网膜水平。为我们 第二个目的，将分析尸检眼mRNA，以确定哪些致病途径是活性的 在受损地区。另外，将使用组织学和形态计量学方法来确定 视网膜神经节细胞和神经纤维层损害的量，并且与激活的相关性 致病途径。还将评估组织视神经变性和凋亡。这 第三个目的是开发一个超长的作用药物输送系统，以治疗耐药性CMV 视网膜炎。我们已经确定了Cidofovir和抗病毒无环核苷的某些衍生物 磷酸盐在体外对HCMV的高度活性，即使病毒抗性的情况通常 使用的抗CMV化合物。我们将使用一种新型的脂质衍生化方法来结晶这些 药物可以长时间释放并在眼睛中溶解。毒性和药代动力学将是 在视网膜炎模型中进行了优化和测试，作为未来临床试验的先驱。