Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Oxford Eye Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.
JAMA Ophthalmol. 2021 Mar 1;139(3):319-328. doi: 10.1001/jamaophthalmol.2020.6418.
Many common inherited retinal diseases are not easily treated with gene therapy. Gene editing with base editors may allow the targeted repair of single-nucleotide transition variants in DNA and RNA. It is unknown how many patients have pathogenic variants that are correctable with a base editing strategy.
To assess the prevalence and spectrum of pathogenic single-nucleotide variants amenable to base editing in common large recessively inherited genes that are associated with inherited retinal degeneration.
DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cross-sectional study, nonidentifiable records of patients with biallelic pathogenic variants of genes associated with inherited retinal degeneration between July 2013 and December 2019 were analyzed using data from the Oxford University Hospitals Medical Genetics Laboratories, the Leiden Open Variation Database, and previously published studies. Six candidate genes (ABCA4, CDH23, CEP290, EYS, MYO7A, and USH2A), which were determined to be the most common recessive genes with coding sequences not deliverable in a single adeno-associated viral vector, were examined. Data were analyzed from April 16 to May 11, 2020.
Proportion of alleles with a pathogenic transition variant that is potentially correctable with a base editing strategy and proportion of patients with a base-editable allele.
A total of 12 369 alleles from the Leiden Open Variation Database and 179 patients who received diagnoses through the genetic service of the Oxford University Hospitals Medical Genetics Laboratories were analyzed. Editable variants accounted for 53% of all pathogenic variants in the candidate genes contained in the Leiden Open Variation Database. The proportion of pathogenic alleles that were editable varied by gene; 63.1% of alleles in ABCA4, 62.7% of alleles in CDH23, 53.8% of alleles in MYO7A, 41.6% of alleles in CEP290, 37.3% of alleles in USH2A, and 22.2% of alleles in EYS were editable. The 5 most common editable pathogenic variants of each gene accounted for a mean (SD) of 19.1% (9.5%) of all pathogenic alleles within each gene. In the Oxford cohort, 136 of 179 patients (76.0%) had at least 1 editable allele. A total of 53 of 107 patients (49.5%) with biallelic pathogenic variants in the gene ABCA4 and 16 of 56 patients (28.6%) with biallelic pathogenic variants in the gene USH2A had 1 of the 5 most common editable alleles.
This study found that pathogenic variants amenable to base editing commonly occur in inherited retinal degeneration. These findings, if generalized to other cohorts, provide an approach for developing base editing therapies to treat retinal degeneration not amenable to gene therapy.
许多常见的遗传性视网膜疾病不易通过基因疗法治疗。碱基编辑器的基因编辑可能允许靶向修复 DNA 和 RNA 中的单核苷酸转换变体。尚不清楚有多少患者的致病性变体可以通过碱基编辑策略纠正。
评估常见隐性遗传性视网膜变性相关大基因中可通过碱基编辑纠正的致病性单核苷酸变体的流行率和谱。
设计、设置和参与者：在这项回顾性横断面研究中，使用牛津大学医院医学遗传学实验室、莱顿开放变异数据库和先前发表的研究中的数据，分析了 2013 年 7 月至 2019 年 12 月期间双等位基因致病性变体患者的非识别记录，这些患者的基因与遗传性视网膜变性相关。研究了 6 个候选基因（ABCA4、CDH23、CEP290、EYS、MYO7A 和 USH2A），这些基因被确定为最常见的隐性基因，其编码序列无法在单个腺相关病毒载体中传递。
具有碱基编辑策略潜在可纠正的致病性转换变体的等位基因比例和具有碱基可编辑等位基因的患者比例。
分析了来自莱顿开放变异数据库的 12369 个等位基因和通过牛津大学医院医学遗传学实验室遗传服务诊断的 179 名患者。在莱顿开放变异数据库中包含的候选基因中，碱基编辑变体占所有致病性变体的 53%。致病性等位基因的可编辑性因基因而异；ABCA4 中的 63.1%、CDH23 中的 62.7%、MYO7A 中的 53.8%、CEP290 中的 41.6%、USH2A 中的 37.3%和 EYS 中的 22.2%的等位基因是可编辑的。每个基因的 5 个最常见的可编辑致病性变体平均（SD）占每个基因中所有致病性等位基因的 19.1%（9.5%）。在牛津队列中，179 名患者中的 136 名（76.0%）至少有 1 个可编辑等位基因。ABCA4 基因中 53 名（49.5%）具有双等位基因致病性变体的 107 名患者和 USH2A 基因中 16 名（28.6%）具有双等位基因致病性变体的患者具有 5 个最常见的可编辑等位基因之一。
本研究发现，可通过碱基编辑纠正的致病性变体在遗传性视网膜变性中常见。如果这些发现推广到其他队列，将为开发碱基编辑疗法治疗不能通过基因疗法治疗的视网膜变性提供一种方法。
