一项开放标签 II 期研究,评估对脉络膜血症患者双侧相继施用视网膜基因疗法的安全性:GEMINI 研究。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-08-01 Epub Date: 2024-07-27 DOI:10.1089/hum.2024.017
Robert E MacLaren, Isabelle Audo, M Dominik Fischer, Rachel M Huckfeldt, Byron L Lam, Mark E Pennesi, Robert Sisk, James A Gow, Jiang Li, Kan Zhu, So-Fai Tsang
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引用次数: 0

摘要

脉络膜血症是一种无法治愈的进行性视网膜变性疾病,主要影响年轻男性,会导致视力丧失。GEMINI是一项多中心、开放标签、前瞻性、两期、介入性II期研究,评估基因疗法timrepigene emparvovec在基因确诊脉络膜血症成年男性患者中双侧连续给药的安全性(NCT03507686,ClinicalTrials.gov)。Timrepigene emparvovec是一种腺相关病毒2(AAV2)载体,编码Rab护送蛋白1(REP1)的cDNA,并由下游的木鸡肝炎病毒转录后调控元件(WPRE)增强。在进行玻璃体切除和视网膜剥离后,通过视网膜下注射的方式注入含有 1×1011 个载体基因组的 0.1 mL Timrepigene emparvovec。第二只眼在手术 12 个月后接受治疗。在 12 个月的时间里,对每只眼睛进行了多达 9 次的随访。共有 66 人接受了 Timrepigene emparvovec 治疗,其中 53 人完成了研究。即使在双侧视网膜脱离和视网膜下注射后,双眼视力仍能保持,不受手术窗口期长短的影响。双侧治疗耐受性良好,主要出现轻度或中度治疗突发不良事件(TEAE),严重手术并发症发生率较低(7.6%)。45.5%的参与者报告了视网膜炎症TEAEs,双眼的发生率相似;事后分析发现,与基线相比,这些TEAEs与第12个月的临床显著视力下降无关。两名参与者(3.0%)报告了严重的非感染性视网膜炎。在注射第二只眼睛时,之前接触过 Timrepigene emparvovec 不会增加发生严重 TEAEs 或严重眼部 TEAEs 的风险;此外,也未观察到全身性免疫反应或接种效应。基线存在抗载体中和抗体可能与注射第一只眼睛后眼部炎症或视力下降相关的 TEAE 百分比较高有关。GEMINI研究的结果可能会为其他视网膜疾病基因疗法的双侧连续给药决策提供参考。
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An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus serotype 2 vector encoding the cDNA of Rab escort protein 1, augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element. Up to 0.1 mL of timrepigene emparvovec, containing 1 × 1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intrasurgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec, and 53 completed the study. Visual acuity (VA) was generally maintained in both eyes, independent of intrasurgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post hoc analyses found that these were not associated with clinically significant vision loss at month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of antivector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced VA after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
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