First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia
First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia
复制标题
AAV8-hCARp.hCNGB3 在患有 CNGB3 相关色盲的成人和儿童中的首次人体基因治疗试验
DOI：
10.1016/j.ajo.2023.05.009
复制
发表时间：
2023
影响因子：
4.2
通讯作者：
Michaelides M
中科院分区：
文献类型：
--
作者：
Michaelides M
目的评估AAV 8-hCARp.hCNGB3治疗CNGB 3相关性色盲（ACHM）患者的安全性和有效性。设计前瞻性、1/2期（NCT 03001310）、开放标签、非随机临床试验。在剂量递增阶段，成人参与者在视力最差的眼睛中施用3种AAV 8-hCARp.hCNGB3剂量水平中的1种（高达0.5 mL）。在成人中确定最大耐受剂量后，在≥3岁儿童中进行扩展期。所有参与者均接受局部和口服皮质类固醇。安全性和有效性参数，包括治疗相关的不良事件和视力，视网膜敏感性，色觉，和光敏感性，进行了评估6 month. ResultsAAV 8-hCARp.hCNGB3（11名成人，12名儿童）是安全的，一般耐受性良好。23名参与者中有9名发生眼内炎症，严重程度主要为轻度或中度。重度病例主要发生在最高剂量下。2起事件被认为是严重和剂量限制性事件。所有眼内炎症均在局部和全身类固醇治疗后消退。对于任何疗效评估，从基线至第24周的变化模式均不一致。然而，在几项评估中，个体参与者观察到了有利的变化，包括色觉（n = 6/23），光厌恶（n = 11/20）和视觉相关生活质量问卷（n = 21/23）。结论AAV 8-hCARp.hCNGB3用于CNGB 3相关ACHM表现出可接受的安全性和耐受性。几个疗效参数的改善表明AAV 8-hCARp.hCNGB3基因治疗可能提供益处。这些发现，以及其他敏感和定量终点的发展，支持继续研究。
PurposeTo assess the safety and efficacy of AAV8-hCARp.hCNGB3in participants withCNGB3-associated achromatopsia (ACHM).DesignProspective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial.MethodsThe study enrolled 23 adults and children withCNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months.ResultsAAV8-hCARp.hCNGB3(11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23).ConclusionsAAV8-hCARp.hCNGB3forCNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.