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Abstract：
This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV).
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1.
Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%).
AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up.
This systematic review will help to inform and guide future clinical trials.
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1.
Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%).
AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up.
This systematic review will help to inform and guide future clinical trials.
摘要：
■本系统综述评估了使用腺相关病毒（AAV）进行眼部基因治疗的安全性和有效性。
■MEDLINE,Embase,Cochrane中央控制试验登记册,和ClinicalTrials.gov进行了系统的搜索，以使用与视网膜疾病相关的关键词进行控制或非控制的介入基因治疗研究，基因治疗,和AAV载体。主要结果指标是安全性，基于眼部严重不良事件（SAE）。次要结果指标根据最佳矫正视力（BCVA）和眼部分娩后视觉敏感性和全身受累的改善来评估治疗的疗效。使用DerSimonianLaird随机效应模型进行汇集。使用Cochrane偏差风险工具评估偏差风险，版本1。
■我们的搜索确定了3548条记录。其中,80份出版物符合资格标准，代表28项注册临床试验和5项涉及AAV基因治疗Leber先天性黑蒙（LCA）的上市后监测研究，脉络膜炎,Leber遗传性视神经病变（LHON），年龄相关性黄斑变性（AMD），视网膜色素变性（RP），X-连锁视网膜裂,和色盲.总的来说,AAV治疗载体与8%的至少一种SAE的累积发生率相关(5%至12%的95%置信区间[CI])。SAE通常与外科手术而不是治疗载体本身相关。不良事件（AE）的不良或不一致报告是荟萃分析的局限性。BCVA和视觉敏感度有任何改善的患者比例为41％（95％CI为31％至51％）和51％（95％CI为31％至70％），分别。全身免疫受累的累积发生率为31％（95％CI=21％至42％）。
■AAV基因治疗载体似乎是安全的，但递送它们所需的外科手术与一些风险相关。疗效的巨大差异可以归因于治疗的患者数量少，人口的异质性和剂量的变异性，volume,和后续行动。
■本系统综述将有助于为未来的临床试验提供信息和指导。
■MEDLINE,Embase,Cochrane中央控制试验登记册,和ClinicalTrials.gov进行了系统的搜索，以使用与视网膜疾病相关的关键词进行控制或非控制的介入基因治疗研究，基因治疗,和AAV载体。主要结果指标是安全性，基于眼部严重不良事件（SAE）。次要结果指标根据最佳矫正视力（BCVA）和眼部分娩后视觉敏感性和全身受累的改善来评估治疗的疗效。使用DerSimonianLaird随机效应模型进行汇集。使用Cochrane偏差风险工具评估偏差风险，版本1。
■我们的搜索确定了3548条记录。其中,80份出版物符合资格标准，代表28项注册临床试验和5项涉及AAV基因治疗Leber先天性黑蒙（LCA）的上市后监测研究，脉络膜炎,Leber遗传性视神经病变（LHON），年龄相关性黄斑变性（AMD），视网膜色素变性（RP），X-连锁视网膜裂,和色盲.总的来说,AAV治疗载体与8%的至少一种SAE的累积发生率相关(5%至12%的95%置信区间[CI])。SAE通常与外科手术而不是治疗载体本身相关。不良事件（AE）的不良或不一致报告是荟萃分析的局限性。BCVA和视觉敏感度有任何改善的患者比例为41％（95％CI为31％至51％）和51％（95％CI为31％至70％），分别。全身免疫受累的累积发生率为31％（95％CI=21％至42％）。
■AAV基因治疗载体似乎是安全的，但递送它们所需的外科手术与一些风险相关。疗效的巨大差异可以归因于治疗的患者数量少，人口的异质性和剂量的变异性，volume,和后续行动。
■本系统综述将有助于为未来的临床试验提供信息和指导。
