Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial.
Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial.
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DOI：
10.1001/jamaophthalmol.2013.7971
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发表时间：
2014-04-01
影响因子：
8.1
通讯作者：
Guy, John
中科院分区：
文献类型：
--
作者：
Lam, Byron L.;Feuer, William J.;Schiffman, Joyce C.;Porciatti, Vittorio;Vandenbroucke, Ruth;Rosa, Potyra R.;Gregori, Giovanni;Guy, John
建立G11778 A Leber遗传性视神经病变（LHON）的自然史对于确定最佳终点以评估计划的基因治疗试验的安全性和有效性非常重要。利用目前G11778 A LHON患者自然史研究的结果，计划一项基因治疗临床试验，该试验将通过注射到玻璃体中的腺相关病毒载体，将正常核编码的ND 4基因递送到视网膜神经节细胞核中，从而使用异位表达。2008年启动的一项前瞻性观察性研究在初级和转诊机构实践环境中进行。参与者包括2008年9月至2012年3月招募的44名G11778 A LHON患者，每6个月进行一次评估，并于2012年8月返回进行1次或多次随访（6-36个月）。全面的神经眼科检查及主要措施。视力，自动视野测试，图形视网膜电图和光谱域光学相干断层扫描。在随访期间，临床指标稳定，视力与用于监测患者的其他视觉因素一样好或更好。根据早期治疗糖尿病视网膜病变研究图表中15个或更多字母的标准，8名患者（18%）的13只眼睛得到改善，但在症状发作后24个月，任何进一步的改善都不超过20/100。视力恢复发生在一些患者中，尽管持续显着的视网膜神经纤维层变薄，与视力未恢复的患者难以区分。G11778 A LHON患者视力的自发改善并不常见，并且在发生时是部分和有限的，因此用合成野生型ND 4亚基基因的腺相关病毒介导的基因治疗改善视力应该可以用合理的样本量检测。视力似乎是计划临床试验最合适的主要终点。
Establishing the natural history of G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points to assess the safety and efficacy of a planned gene therapy trial. To use the results of the present natural history study of patients with G11778A LHON to plan a gene therapy clinical trial 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. A prospective observational study initiated in 2008 was conducted in primary and referral institutional practice settings. Participants included 44 individuals with G11778A LHON, recruited between September 2008 and March 2012, who were evaluated every 6 months and returned for 1 or more follow-up visits (6–36 months) as of August 2012. Complete neuro-ophthalmic examination and main measures. Visual acuity, automated visual field testing, pattern electroretinogram, and spectral-domain optical coherence tomography. Clinical measures were stable during the follow-up period, and visual acuity was as good as or better than the other visual factors used for monitoring patients. Based on a criterion of 15 or more letters from the Early Treatment Diabetic Retinopathy Study chart, 13 eyes of 8 patients (18%) improved, but 24 months after the onset of symptoms, any further improvements were to no better than 20/100. Acuity recovery occurred in some patients despite continued marked retinal nerve fiber layer thinning indistinguishable from that in patients who did not recover visual acuity. Spontaneous improvement of visual acuity in patients with G11778A LHON is not common and is partial and limited when it occurs, so improvements in vision with adeno-associated virus–mediated gene therapy of a synthetic wild-type ND4 subunit gene should be possible to detect with a reasonable sample size. Visual acuity appears to be the most suitable primary end point for the planned clinical trial.
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影响因子：
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作者：
Koilkonda, Rajeshwari D.;Chou, Tsung-Han;Porciatti, Vittorio;Hauswirth, William W.;Guy, John
通讯作者：
Guy, John
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