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：
10408112
负责人：
Jason Comander
金额：
$ 41.23万
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/10408112
关键词：
Address Amino Acids Antisense Oligonucleotides Benign Biochemical Biological Assay Blindness Cells Collection DNA Data Data Set Deposition Detection Diagnosis Disease Dose 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 Pharmacology 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 base 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 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.

项目摘要/摘要尽管在基因检测遗传性视网膜变性（IRD）方面取得了进步未知的意义（VU）可以证明患者接受遗传诊断。支撑研究是使用基于细胞的测定方法来解决此问题的研究变体是引起疾病的突变，并且是良性多态性的，在Atale会产生可靠的信息是造成视力丧失的重要原因基因特异性疗法，例如基因疗法，而本人遗传诊断至关重在施用基因特异性疗法之前，对特定通畅的遗传原因有信心识别 IRD可以是Difficalt，大约有三分之一的患者接受了遗传诊断。是一个空前的数字，可以有效地识别IRD的遗传因果，以翻译现有和对患者的新兴视力或视力更高的疗法。研究是通过一系列集成目标来利用机会统一，着重于效率识别重要的IRD基因中的病原体变异旨在改变原始研究范式 - 分析发现IRD基因中的少量DNA变异 - 发现范式是否会事先就医学上重要的IRD基因的变异产生大量数据。因此，支撑研究检验了以下假设，即基于经验的基于细胞的测定可以有效地进行。准确地识别人类中哪些DNA变体是致病性的，并引起IRD，哪些可能是 AIM 1中的良性多态性。致病氨基酸在重要的IRD基因中变化。这些突变中的哪个是针对小分子的可及性疗法。经过修改以表征全面的潜在致病性氨基酸的集合，并在一个人中变化一个人是一个人，一个人重要的IRD基因，RPE65。表型数据将定义适当的数值范围，这些范围会导致人类观察。这些目标共同为生产公开可用的资源提供了一种途径，该资源可以立即提供有关VUS IRD的更高形式的信息信息与医学遗传学家以及 IRDS。医疗服务的信息导致将疗法提供给其他不可治疗的患者。