PDF(Pubmed)
Abstract：
OBJECTIVE: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy\'s current state of the art.
METHODS: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.
METHODS: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.
摘要：
目的：基因治疗实际上似乎在治疗Leber先天性黑蒙和一些不同的遗传性视网膜疾病（IRD）方面取得了有希望的结果；该策略的主要目标是用DNA序列中没有缺陷的野生型基因改变基因缺陷，以实现光感受器功能的部分恢复，因此,部分恢复失去的视网膜功能。这种方法导致了一种新药（voretigeneneparvovovec-rzyl）的引入，用于在患有Leber先天性黑蒙（LCA）的患者中替代RPE65基因；然而，由于缺乏正确评估残余光感受器的解剖和功能状况，因此治疗结果不恒定，并且具有可变的持久效果。这些变化也可能与宿主对腺病毒相关载体的免疫反应有关。广泛的视网膜营养不良经常引起怀疑，该疾病或患者是否是成功的基因治疗的良好候选者。因为,经常,不同的疾病具有相似的遗传特征，导致同一家族内临床特征之间不恒定的基因型/表型相关性。例如,RPE65基因上的突变导致Leber先天性黑蒙（LCA）以及某些形式的色素性视网膜炎（RP），BardetBiedl综合征（BBS），先天性固定夜盲（CSNB）和Usher综合征（USH），具有非常广泛的临床表现。这些令人困惑的因素是由于产品蛋白质（类维生素A异构体水解酶）所涉及的不同途径，因此,视网膜功能的重叠代谢。考虑到这一点和药物的成本（超过十万美元），必须遵循指南或算法来评估最适合的疾病和候选患者,以最大化输出.不幸的是,此刻,没有关于谁用基因疗法治疗的建议。此外，基因治疗可能有助于其他形式的遗传性视网膜营养不良，随着疾病发病率的增加和功能状况的改善(实际上，基因治疗仅适用于视力不佳的患者，考虑到由于治疗程序可能产生的副作用)，这种方法可以带来更好的功能，希望,视觉恢复。但是,在这个观点中,可能是接受基因治疗的疾病候选者或患者，与几种不同形式的IRD的临床试验开始有关？此外，能够正确选择患者的测试的黄金标准是什么？我们的工作旨在评估仪器形态功能测试的临床考虑因素，以评估治疗的候选受试者，并将其与临床和遗传缺陷分析相关联，经常,不是通讯员。我们试图定义哪些参数是选择IRD患者进行基因治疗的临床基本原理的重要组成部分。这篇综述将描述一系列用于从测试中表征视网膜形态和功能的模型，如光学相干断层扫描（OCT）和电生理评估（ERG），并将其作为临床试验的主要结果进行评估。次要目的是根据基因治疗的最新技术提出IRD的辅助临床分类及其可及性。
方法：OCT，ERG,在不同形式的IRD中进行视野检查，根据临床和视网膜状况进行分类；与基因缺陷分类相比，我们利用一种基于患者视网膜形态功能信息的临床分类诊断算法，这可以显著提高诊断准确性，因此,帮助眼科医生做出正确的诊断，以达到最佳的临床效果。这些考虑因素对于选择可能对基因治疗有可能的治疗成功的IRD患者非常有帮助，并过滤掉那些由于视网膜状况不好而治疗机会较低或没有阳性结果机会的患者。避免耗时的患者管理与不满意的结果。
方法：OCT，ERG,在不同形式的IRD中进行视野检查，根据临床和视网膜状况进行分类；与基因缺陷分类相比，我们利用一种基于患者视网膜形态功能信息的临床分类诊断算法，这可以显著提高诊断准确性，因此,帮助眼科医生做出正确的诊断，以达到最佳的临床效果。这些考虑因素对于选择可能对基因治疗有可能的治疗成功的IRD患者非常有帮助，并过滤掉那些由于视网膜状况不好而治疗机会较低或没有阳性结果机会的患者。避免耗时的患者管理与不满意的结果。
