Improving the throughput of diagnosis and treatment of inherited diseases of the retina

提高视网膜遗传性疾病的诊断和治疗效率

基本信息

批准号：
10629340
负责人：
Jason Comander
金额：
$ 42.5万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629340
关键词：
Address Amino Acids Antisense Oligonucleotide Therapy Benign Biochemical Biological Assay Blindness Calibration Cells Classification Collection DNA Data Data Analyses Data Set Deposition Detection Diagnosis Disease Dose Eligibility Determination Etiology FDA approved Genes Genetic Genetic Polymorphism Goals Hereditary Disease Human Inherited Investigation Knowledge Measures Medical Molecular Chaperones Mutation Outcome Pathogenicity Pathway interactions Patients Pharmacogenomics RPE65 protein Recording of previous events Research Research Personnel Resources Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Techniques Testing Time Toxic effect Translating Validation Variant Vision Work disability disease-causing mutation experience experimental study gene augmentation therapy gene therapy genetic counselor genetic disorder diagnosis genetic testing improved inherited retinal degeneration interest large datasets pharmacologic phenotypic data preservation prevent proband protein folding prototype public database response retinol isomerase sight restoration small molecule variant of unknown significance

项目摘要

Project Summary/Abstract Despite advances in genetic testing for inherited retinal degenerations (IRDs), detection of a DNA variant of unknown significance (VUS) can prevent a patient from receiving a genetic diagnosis. The long-term goal of the proposed research is to address this problem using cell-based assays that can efficiently identify which DNA variants are disease-causing mutations and which are benign polymorphisms, at a scale that would produce medically-actionable information. IRDs are important causes of vision loss, and are increasingly treatable by gene-specific therapies such as gene augmentation therapy. While an accurate genetic diagnosis is critical before administering a gene-specific therapy, confident identification of the genetic cause for particular patient’s IRD can be difficult, with about one third of patients failing to receive a genetic diagnosis altogether. Thus, there is an unprecedented need to efficiently identify the genetic causality of IRDs in order to translate existing and emerging sight-preserving or sight-restoring therapies to patients. To address this need, the goal of the proposed research is to capitalize on this opportunity via a set of integrated Aims focused on the efficient identification of pathogenic variants in important IRD genes. The proposed research seeks to shift the current research paradigm-- analyzing small numbers of DNA variants in IRD genes as they are discovered-- to a paradigm where large quantities of data are generated in advance about variants in medically-important IRD genes. Therefore, the proposed research tests the hypothesis that empiric, cell-based assays can be used to efficiently and accurately identify which DNA variants in humans are pathogenic and cause IRDs, and which are likely benign polymorphisms. In Aim 1, we assemble and characterize a comprehensive collection of potentially pathogenic amino acid changes in an important dominant IRD gene, rhodopsin. An expansion of this Aim tests which of these mutations are amenable to chaperone therapy with small molecules. In Aim 2, these techniques are modified to characterize a comprehensive collection of potentially pathogenic amino acid changes in an important recessive IRD gene, RPE65. It is further hypothesized that comparing assay results to human phenotype data will define proper numerical ranges which correspond to pathogenic results in humans. Viewed together, these Aims provide a pathway for producing an openly-available resource that could instantly provide higher-fidelity information about VUS in IRDs to medical geneticist, genetic counselors, and investigators of IRDs. It takes advantage of a significant opportunity where investigation of the Aims can directly produce medically-actionable information resulting in the delivery of therapies to otherwise untreatable patients.

项目概要/摘要尽管遗传性视网膜变性 (IRD) 的基因检测取得了进展，但检测到 DNA 变异未知意义（VUS）可能会阻止患者接受基因诊断。拟议的研究是使用基于细胞的检测来解决这个问题，该检测可以有效地识别哪些 DNA 变异是引起疾病的突变，也是良性多态性，其规模会产生 IRD 是导致视力丧失的重要原因，并且越来越可以通过药物治疗。基因特异性疗法，例如基因增强疗法，而准确的基因诊断至关重要。在进行基因特异性治疗之前，自信地识别特定患者的遗传原因 IRD 可能很困难，大约三分之一的患者完全无法接受基因诊断。前所未有地需要有效地识别 IRD 的遗传因果关系，以便转化现有的和为患者提供新兴的视力保护或视力恢复疗法来满足这一需求，是拟议的目标。研究的目的是通过一系列综合目标来利用这一机会，重点是有效识别重要 IRD 基因的致病变异。拟议的研究旨在改变当前的研究。范式——分析 IRD 基因中发现的少量 DNA 变异——到一个范式提前生成有关医学上重要的 IRD 基因变异的大量数据。因此，拟议的研究测试了以下假设：经验性的、基于细胞的测定可用于有效地准确识别人类中哪些 DNA 变异是致病性的并导致 IRD，哪些可能是在目标 1 中，我们收集并表征了潜在的全面集合。重要的显性 IRD 基因视紫红质的致病氨基酸变化是该目的测试的扩展。这些突变中的哪些适合小分子伴侣疗法在目标 2 中，这些技术。被修改以表征潜在致病氨基酸变化的全面集合重要的隐性 IRD 基因，RPE65 进一步发展，将检测结果与人类进行比较。表型数据将定义与人类致病结果相对应的适当数值范围。这些目标共同提供了一条生成公开可用资源的途径，该资源可以立即提供向医学遗传学家、遗传咨询师和研究人员提供有关 IRD 中 VUS 的更高保真度信息 IRD 利用了一个重要的机会，即对目标的调查可以直接产生结果。医学上可行的信息，从而为无法治疗的患者提供治疗。