Preclinical and Clinical Development of Treatment for X-linked Retinoschisis

X连锁视网膜劈裂治疗的临床前和临床进展

• 批准号: 7966986
• 负责人: Paul Sieving
• 金额: $ 48.68万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966986
• 关键词: Address; Adolescent; Affect; Age related macular degeneration; Animal Genetics; Animal Model; Animals; Binding; Biochemistry; Blood; Cell membrane; Characteristics; Clinic; Clinical; Clinical Protocols; Clinical Trials; Consent; Diagnosis; Disease; Disease Progression; Dose; Electron Microscopy; Electroretinography; Enrollment; Failure; Family member; Female; Functional disorder; Gene Transfer; Genes; Genetic; Genetic Models; Genotype; Goals; Human; Human Genetics; Immunohistochemistry; Inherited; Intervention; Laboratories; Lead; Light; Longitudinal Studies; Macular degeneration; Maps; Measures; Membrane; Membrane Proteins; Metric; Molecular Biology; Molecular Genetics; Mothers; Mus; Mutation; Nature; Neurodegenerative Disorders; Neurons; Ophthalmic examination and evaluation; Patients; Phenotype; Phospholipids; Photoreceptors; Physiological; Promoter Regions; Proteins; Registries; Retina; Retinal; Retinal Diseases; Retinitis Pigmentosa; Retinoschisis; Rodent; Role; Signal Transduction; Site; Source; Structure; Synapses; Targeted Research; Techniques; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Translational Research; United States National Institutes of Health; Viral; Viral Vector; Vision; Work; X Chromosome; X-Linked Retinoschisis; XLRS1 protein; adeno-associated viral vector; base; behavior measurement; cohort; design; human disease; human male; inherited retinal degeneration; male; mouse model; pre-clinical; research study; study characteristics; success; therapy development

This laboratory is appropriately titled Translational Research, as we use inherited retinal degenerations identified in the clinic as both a source of clues about retinal function and dysfunction and a target for research in therapeutic intervention. Our goal is to develop therapy for human genetic retinal neurodegenerative diseases, by studying animal models that mimic the human disease state and then use these findings to develop clinical trials of therapeutic agents. We use normal rodents and rodents that are genetically altered to mimic human retinal disease to study the characteristics (phenotype), molecular genetics, physiological mechanisms and possible treatments of inherited retinal degenerations. Our laboratory applies the techniques of light and electron microscopy, immunohistochemistry, biochemistry, and molecular biology to human and animal retinal tissue, as well as the electroretinogram (ERG) and behavioral measurements to access retinal function in animals in ways similar to those used to evaluate human vision in the clinic. These studies address human conditions of retinal and macular degenerations and age-related macular degeneration. Current efforts focus on human X-linked juvenile retinoschisis (XLRS). XLRS is an inherited disease and is a leading cause of juvenile macular degeneration in human males. It is due to mutations in the retinoschisin gene found on the X chromosome. We are working to understand the disease mechanisms that bring about retinal structural changes and neuronal synaptic signaling deficiency in a mouse model created in this laboratory section. At the same time, we are developing gene transfer therapy using a viral vector to supply a normal copy of the retinoschisin gene to the retina of patients in which it is defective. . Our current understanding is based on a study of human affected patients and on analysis of the XLRS mouse model. We have probed the biochemistry and sub-cellular localization of the retinoschisin protein and have localized RS to particular cell membrane sites of photoreceptors and synapses and measured changes in key membrane proteins in synapses. We discovered molecular interactions between retinoschisin and photoreceptor membrane phospholipids that may explain its role in neuronal structure and retinal signaling. We cloned and characterized the human gene promoter region and have identified the key regulatory sites. A detailed study of long-term disease progression in the XLRS mouse revealed significant correlations between degenerative structural changes and functional neuronal signaling abnormalities. Such studies currently are not possible in human and provide us better understanding of disease mechanisms and give clues on designing appropriate endpoint metrics for eventual human clinical trial. We showed retinal rescue of structure and function in the XLRS mouse by viral (AAV) vector retinoschisin gene transfer, and we are now characterizing appropriate intervention times in disease progression, doses and other parameters that lead to success or failure of gene transfer. We are also disigning and preparing a human AAV- retinoschisin gene transfer experiment. Clinical protocol: Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis ClinicalTrials.gov Identifier: NCT00055029 The objectives of this registry are to understand the nature of the XLRS disease in order to develop appropriate treatments by characterizing the anatomical and functional characteristics of retinoschisis and ultimately generate a well-documented genotype-phenotype correlation map. A minimum of 100 males diagnosed with X-linked retinoschisis will undergo clinical examination and have their blood drawn for genotyping. Blood will also be drawn from available and consenting mothers of affected males. An eye examination will be performed and blood drawn from any symptomatic available and consenting female family members. A maximum of 500 affected males and family members may be enrolled. Sites outside of NIH are participating as referral centers to accumulate the cohort.

该实验室的标题为转化研究，因为我们使用诊所中确定的遗传性视网膜退化是有关视网膜功能和功能障碍的线索来源，也是治疗干预研究的目标。我们的目标是通过研究模仿人类疾病状态的动物模型，然后使用这些发现来开发治疗剂的临床试验，来开发人类遗传性视网膜神经退行性疾病的治疗。我们使用对模拟人类视网膜疾病的基因改变的正常啮齿动物和啮齿动物来研究特征（表型），分子遗传学，生理机制以及遗传性视网膜变性的可能治疗方法。我们的实验室将光和电子显微镜，免疫组织化学，生物化学和分子生物学应用于人类和动物视网膜组织，以及电子图（ERG）以及行为测量以及与在临时型人类视野中相似的动物中访问视网膜功能的行为测量。这些研究涉及视网膜和黄斑变性以及与年龄相关的黄斑变性的人类条件。 当前的努力集中在人类X连锁的少年视网膜（XLR）上。 XLRS是一种遗传性疾病，是男性少年黄斑变性的主要原因。这是由于在X染色体上发现的视网膜感染素基因中的突变。我们正在努力理解在本实验室部分创建的小鼠模型中导致视网膜结构变化和神经元突触信号不足的疾病机制。同时，我们正在使用病毒载体开发基因转移疗法，以向视网膜感染基因的正常副本提供其缺陷患者的视网膜。 。 我们目前的理解是基于对人类受影响患者的研究和XLRS小鼠模型的分析。我们已经探测了视网膜蛋白的生物化学和亚细胞定位，并将RS局部局部到感光体和突触的特定细胞膜位点，并测量了突触中关键膜蛋白的变化。我们发现了视网膜气概与感光膜磷脂之间的分子相互作用，这些磷脂可能解释了其在神经元结构和视网膜信号传导中的作用。我们克隆并表征了人类基因启动子区域，并确定了关键的调节位点。 XLRS小鼠长期疾病进展的详细研究表明，退化性结构变化与功能性神经元信号异常之间存在显着相关性。目前，此类研究在人类中是不可能的，并为我们提供了对疾病机制的更好理解，并提供了设计适当的终点指标以最终人类临床试验的线索。我们通过病毒（AAV）载体视网膜感染基因转移表现出了视网膜的结构和功能，我们现在正在表征适当的干预时间，导致基因转移成功或失败的疾病进展，剂量和其他参数。我们还在不符合和准备人类的拟南芥基因转移实验。 临床方案： X连锁少年视网膜的临床和遗传研究 临床标识符：NCT00055029 该注册表的目的是了解XLRS疾病的性质，以通过表征视网膜的解剖学和功能特征来开发适当的治疗方法，并最终产生有据可查的基因型 - 原型相关图。至少有100名被诊断为X连锁视网膜静脉曲子的男性将接受临床检查，并吸收其血液进行基因分型。血液也将从可用的和同意的男性母亲中得知。将进行眼科检查，并从任何有症状的女性家庭成员中抽血。最多可能会招募500名受影响的男性和家庭成员。 NIH以外的地点是作为推荐中心的参与，以积累该队列。