Scheie Eye Institute at the Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania; The Center for Advanced Retinal & Ocular Therapeutics, Philadelphia, Pennsylvania; The Children's Hospital of Philadelphia, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
Ophthalmology. 2022 Oct;129(10):1177-1191. doi: 10.1016/j.ophtha.2022.06.006. Epub 2022 Jun 15.
To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM.
Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial.
Fifteen CHM patients (ages 20-57 years at dosing).
Patients received uniocular subfoveal injections of low-dose (up to 5 × 10 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 10 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing.
Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF).
We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships.
Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.
评估携带人脉络膜视网膜炎（CHM）编码 cDNA 的重组腺相关病毒血清型 2（AAV2）载体亚视网膜递送至 CHM 中的安全性。
前瞻性、开放标签、非随机、剂量递增、I/II 期临床研究。
15 名 CHM 患者（给药时年龄 20-57 岁）。
患者接受单眼黄斑下腔低剂量（每只眼最多 5×10 个载体基因组 [vg]，n=5）或高剂量（每只眼最多 1×10 vg，n=10）的携带人 CHM 编码 cDNA 的重组腺相关病毒血清型 2（AAV2）载体（AAV2-hCHM）。患者在术前和术后 2 年内接受眼科检查、多模态视网膜成像和心理物理测试。
视力、视野（10-2 方案）、光谱域 OCT（SD-OCT）和短波长眼底自发荧光（SW-FAF）。
我们未发现与载体相关或全身性毒性。除 2 例患者外（1 例发生急性黄斑变薄，1 例发生黄斑裂孔），所有患者的视力均恢复至基线 15 个字母以内；其余患者在 2 年内未见黄斑中心凹结构的明显变化。干预眼和对照眼的平均光适应敏感度通过视野检查或 SD-OCT 和 SW-FAF 视网膜色素上皮相对保留的外侧范围无显著差异。微视野检查显示，在一些位置和参与者的干预眼中，敏感性有轻微但无统计学意义的（< 3 次就诊变异性的标准差）增益。没有明显的剂量依赖性关系。
在 15 名患者中，13 名患者接受黄斑下腔 AAV2-hCHM 注射后，视力在基线 15 个字母以内。1 名患者出现急性黄斑变薄，黄斑功能无改变，1 名患者出现黄斑裂孔，提示黄斑对视网膜下注射敏感。更长的观察间隔将有助于确定干预眼和对照眼之间观察到的敏感性和疾病进展率的细微差异的意义。
