Lam Byron L, Feuer William J, Abukhalil Fawzi, Porciatti Vittorio, Hauswirth William W, Guy John
Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Arch Ophthalmol. 2010 Sep;128(9):1129-35. doi: 10.1001/archophthalmol.2010.201.
To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous.
Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3.
Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 μm up to 32 months after visual loss. It was 63.5 μm for all affected patients and 100.7 μm for carriers (P < .01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P < .01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than -2 dB, and average RNFL thickness more than 80 μm.
Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers.
描述莱伯遗传性视神经病变（LHON）基因治疗临床试验第1年的患者概况。本研究旨在识别和表征线粒体DNA中携带G11778A突变的患病患者和携带者，以便进行计划中的基因治疗，该治疗将通过向玻璃体注射腺相关病毒载体，将正常的核编码ND4基因导入视网膜神经节细胞核中，采用“异位表达”。
对患有视力丧失的LHON患者以及无症状的母系亲属进行线粒体DNA中通常与LHON相关的ND1、ND4和ND6突变的分子筛查。所有患者和母系亲属还接受了完整的神经眼科检查、自动视野测试、图形视网膜电图（PERG）和光学相干断层扫描（OCT3）。
招募了25名患有LHON的受试者和21名线粒体DNA G11778A突变阳性的携带者。在ND4基因中检测到另外三种突变，即G11719A、G11947A或G11914A。视力丧失后长达32个月时，视网膜神经纤维层（RNFL）平均厚度为78.3μm。所有患病患者的该厚度为63.5μm，携带者为100.7μm（P <.01）。患病患者的平均PERG振幅（正常的40%）低于携带者（正常的94%）（P <.01）。四名PERG振幅低于正常75%的携带者，糖尿病视网膜病变早期治疗研究视力大于20/25，平均缺损大于 -2 dB，平均RNFL厚度大于80μm。
如果PERG振幅是这些携带者转化为LHON的预测指标，那么未来基因治疗的潜在候选者可能包括视力丧失后长达32个月、RNFL厚度轻度降低的患病患者，或PERG振幅较低且RNFL厚度正常的携带者。
