目的:评估AAV8-hCARp的安全性和有效性。CNGB3相关色盲(ACHM)参与者的hCNGB3。
方法:前瞻性,相位1/2(NCT03001310),开放标签,非随机临床试验。
方法:该研究招募了23名患有CNGB3相关ACHM的成人和儿童。在剂量递增阶段,成人参与者接受了3例AAV8-hCARp中的1例.在视力较差的眼睛中的hCNGB3剂量水平(高达0.5mL)。在成人确定最大耐受剂量后,在≥3岁的儿童中进行了扩张阶段。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(AE)和视力,视网膜敏感性,色觉,光敏感性评估6个月。
结果:AAV8-hCARp。hCNGB3(11名成人,12名儿童)是安全的,通常耐受性良好。23例参与者中有9例发生了眼内炎症,严重程度主要为轻度或中度。严重病例主要发生在最高剂量。两个事件被认为是严重的和剂量限制性的。所有眼内炎症在局部和全身类固醇后消退。对于任何疗效评估,从基线到第24周没有一致的变化模式。然而,在几次评估中,个体参与者观察到了有利的变化,包括色觉(n=6/23),光线厌恶(n=11/20),和视觉相关生活质量问卷(n=21/23)。
结论:AAV8-hCARp。与CNGB3相关的ACHM的hCNGB3表现出可接受的安全性和耐受性。几个功效参数的改善表明AAV8-hCARp。hCNGB3基因治疗可能提供益处。这些发现,随着其他敏感和定量终点的发展,支持继续调查。
To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with
CNGB3-associated achromatopsia (ACHM).
Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial.
The study enrolled 23 adults and children with
CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose 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.
AAV8-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).
AAV8-hCARp.hCNGB3 for
CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.