选择接受 RPGR 视网膜基因治疗的患者时建立临床试验终点。

Establishing Clinical Trial Endpoints in Selecting Patients for RPGR Retinal Gene Therapy.

机构信息

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

出版信息

Transl Vis Sci Technol. 2024 Sep 3;13(9):18. doi: 10.1167/tvst.13.9.18.

DOI:10.1167/tvst.13.9.18

PMID:39287586

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11412382/

Abstract

PURPOSE

Clinical trials for X-linked retinitis pigmentosa (RP) often assess retinal structure using optical coherence tomography (OCT) and function using microperimetry to evaluate initial eligibility and endpoints. Therefore, we seek to determine which parameters might be most sensitive in screening new patients for enrollment.

METHODS

Thirty-one patients (62 eyes) with confirmed retinitis pigmentosa GTPase regulator (RPGR) mutations attending Oxford Eye Hospital were included in this retrospective analysis. Outer retinal structure was investigated by measuring the remaining ellipsoid zone (EZ) and external limiting membrane (ELM) on OCT. Visual function was evaluated by using 10-2 microperimetry mean sensitivity.

RESULTS

The median age of patients with RPGR was 31 years (interquartile range [IQR] = 22-39 years). For the right and left eyes, respectively, the median EZ length through the foveal section was 921 µm (IQR = 607-1570) and 865 µm (IQR = 508-1442) and median ELM length was 2056 µm (IQR = 1336-2764) and 1860 µm (IQR = 1152-2680). Similarly, the median microperimetry sensitivity (MS) was 2.0 decibel (dB; IQR = 0.4-5.4) and 1.1 dB (IQR = 0.1-5.4). Linear mixed model regression analysis showed that EZ was significantly positively correlated to ELM (P < 0.001, R² = 0.931). EZ and ELM were significantly correlated with the microperimetry sensitivity with exponential relationship (P < 0.001, R² = 0.71 and 0.72, respectively). Using the exponential equation of regression line, EZ below approximately 600 µm (RE = 637 µm, 95% confidence interval [CI] = 397-877, LE = 586 µm, 95% CI = 356-817) results in microperimetry sensitivity of approximately 0 dB. There was high degree of inter-eye symmetry for progression of EZ, ELM, and microperimetry sensitivity. Age was significantly correlated with the analyzed parameters (P < 0.001), although with low R² for each of them.

DISCUSSION

EZ may comprise a surrogate biomarker for prediction of visual function in X-linked RP caused by mutations in RPGR and, in turn, identification of appropriate patients for enrollment in clinical trials. As expected, age plays a role in predicting potential biomarkers and visual function, however, it should not be used to preclude patients for gene therapy due to the poor correlation and heterogeneity of disease onset.

TRANSLATIONAL RELEVANCE

Biomarkers of visual function in RPGR-associated RP may lead to identification of appropriate patients for enrollment in clinical trials.

摘要

目的

常染色体隐性遗传视网膜色素变性（RP）的临床试验通常使用光学相干断层扫描（OCT）评估视网膜结构，使用微视野计评估功能，以评估初始入选标准和终点。因此，我们旨在确定哪些参数在筛查新患者入组时最敏感。

方法

本回顾性分析纳入了 31 名（62 只眼）在牛津眼医院就诊的确诊的 X 连锁视网膜色素变性 GTP 酶调节因子（RPGR）突变患者。通过测量 OCT 中的剩余椭圆体带（EZ）和外界膜（ELM）来研究外视网膜结构。通过使用 10-2 微视野平均敏感度评估视觉功能。

结果

RPGR 患者的中位年龄为 31 岁（四分位距 [IQR] = 22-39 岁）。对于右眼和左眼，EZ 穿过中央凹的长度分别为 921 µm（IQR = 607-1570）和 865 µm（IQR = 508-1442），ELM 长度分别为 2056 µm（IQR = 1336-2764）和 1860 µm（IQR = 1152-2680）。同样，微视野敏感度（MS）的中位数为 2.0 分贝（dB；IQR = 0.4-5.4）和 1.1 dB（IQR = 0.1-5.4）。线性混合模型回归分析显示，EZ 与 ELM 呈显著正相关（P < 0.001，R² = 0.931）。EZ 和 ELM 与微视野敏感度呈显著的指数关系（P < 0.001，R² = 0.71 和 0.72）。使用回归直线的指数方程，EZ 约为 600 µm（RE = 637 µm，95%置信区间 [CI] = 397-877，LE = 586 µm，95% CI = 356-817）时，微视野敏感度约为 0 dB。EZ、ELM 和微视野敏感度的进展具有高度的双眼对称性。年龄与分析参数显著相关（P < 0.001），尽管每个参数的 R²均较低。