Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.
Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.
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DOI：
10.1016/j.ophtha.2015.10.025
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发表时间：
2016-03
期刊：
影响因子：
13.7
通讯作者：
Guy J
中科院分区：
文献类型：
--
作者：
Feuer WJ;Schiffman JC;Davis JL;Porciatti V;Gonzalez P;Koilkonda RD;Yuan H;Lalwani A;Lam BL;Guy J
Leber遗传性视神经病变是一种由编码NADH：泛醌氧化还原酶亚单位4(ND4)的线粒体基因突变引起的以严重和快速进行性视力丧失为特征的疾病。我们已经启动了一项基因治疗试验，以确定在线粒体基因组11778位核苷酸发生G到A突变的患者中，表达正常ND4互补DNA的腺相关病毒载体递增剂量的安全性和耐受性。在这项前瞻性开放试验(NCT02161380)中，研究药物(自互补AAV[scAAV]2(Y444,500,730F)-P1ND4v2)被单侧玻璃体内注射到5名患有G11778A LHON的盲人眼内。4名视力丧失超过12个月的参与者接受了治疗。第五名参与者视力丧失不到12个月。前3名受试者接受低剂量载体(5×109VG)治疗，第4名受试者接受中剂量(2.46×1010VG)治疗。视力丧失不到12个月的第五名参与者接受了低剂量。接受治疗的参与者被跟踪了90到180天，并接受了眼睛和系统的安全性评估，以及视觉结构和功能检查。5名患有G11778A LHON的合法失明患者。视力丧失。通过早期治疗糖尿病视网膜病变研究(ETDRS)眼表测量的视力在前3个月从基线到3个月保持不变。随访90天的2名参与者的视力从手部运动增加到7个字母，1个增加了15个字母，相当于提高了3行。没有人失明，也没有观察到严重的不良反应。较小的不良事件包括一过性眼压升高、暴露性角膜炎、结膜下出血、喉咙痛，以及1名受试者中抗AAV2的中和抗体(NAB)一过性增加。所有血样的病媒DNA均为阴性。在这种线粒体疾病的基于病毒的基因转移的第一阶段试验中，前5名参与者没有观察到严重的安全问题。计划在未来4年对这些参与者和其他参与者进行额外的研究跟踪，以确认这些初步观察结果。
Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 109 vg), and the fourth participant was treated at the medium dose (2.46 × 1010 vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Five legally blind patients with G11778A LHON. Loss of visual acuity. Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.