Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene A Secondary Analysis of a Phase 1/2 Clinical Trial
Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene A Secondary Analysis of a Phase 1/2 Clinical Trial
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DOI：
10.1001/jamaophthalmol.2018.6902
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发表时间：
2019-04-01
影响因子：
8.1
通讯作者：
Thomasson, Nitza
中科院分区：
文献类型：
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作者：
Bouquet, Celine;Clermont, Catherine Vignal;Thomasson, Nitza
目的探讨携带ND 4基因的重组腺相关病毒2（Ad-AIV 2）对眼内炎症反应的影响（rAAV 2/2-ND 4）.设计、设置和参与者rAAV 2/2-ND 4的开放标签、剂量递增的1/2期随机临床试验的次要分析包括2009年2月13日，2014年（首例患者访视）至2017年3月30日（第96周末例患者访视），注射后前2年。年龄大于15岁、确诊为ND 4 Leber遗传性视神经病变（LHON）且视力至少能数手指的患者入组5个队列中的1个。4个剂量队列（各3例患者）接受序贯治疗。干预患者接受递增剂量的rAAV 2/2-ND 4（9 × 10（9）、3 × 10（10）、9 × 10（10）和1.8 × 10（11）病毒基因组/眼）作为单次单侧玻璃体内注射。注射后监测患者96周，定期进行眼部检查，并收集血液样本进行免疫test.Main结果和测量复合眼炎症评分（OIS）计算的基础上，前房细胞和耀斑，玻璃体细胞，并根据葡萄膜炎Nomenclature标准化雾度等级。通过酶联免疫斑点法（细胞免疫反应）、酶联免疫吸附试验（IgG滴度）和荧光素酶试验（中和抗体[NAb]滴度）对全身免疫反应进行定量。结果本分析包括15例患者（平均[SD]年龄，47.9 [17.2]岁; 13例男性和2例女性），入选临床试验的5个队列。13名患者在rAAV 2/2-ND 4给药后发生眼内炎症。在所有剂量下均报告轻度前房炎症和玻璃体炎，所有病例均对治疗有反应。在有特发性葡萄膜炎病史的患者中观察到最大OIS为9.5。总体而言，OIS与给予的病毒剂量无关。治疗前，在房水中未检测到针对AAV 2的NAb。两名患者在基线和治疗后针对AAV 2的细胞免疫应答测试呈阳性。体液免疫应答与给药剂量或患者基线免疫状态无明显相关性。OIS和血清NAb滴度之间没有发现关联。结论和相关性在这项研究中，玻璃体内注射rAAV 2/2-ND 4在LHON患者中是安全的，耐受性良好。进一步的研究可能揭示了对rAAV 2/2-ND 4的局部免疫应答，作为观察到的眼内炎症的潜在解释。
IMPORTANCE Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated.OBJECTIVE To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4).DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 x 10(10) viral genomes per eye.INTERVENTIONS Patients received increasing doses of rAAV2/2-ND4 (9 x 10(9), 3 x 10(10), 9 x 10(10), and 1.8 x 10(11) viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing.MAIN OUTCOMES AND MEASURES A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers).RESULTS The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers.CONCLUSIONS AND RELEVANCE In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.