PDF(Pubmed)
Abstract：
Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients\' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).
摘要：
Bietti结晶性视网膜营养不良是一种遗传性视网膜疾病，由CYP4V2突变引起，导致工作年龄人群失明，目前没有可用的治疗方法。这里,我们报告了Bietti晶体视网膜视网膜营养不良的基因治疗的首次人体临床试验（NCT04722107）的结果，包括12名接受180-365天随访的参与者。这个开放标签，单臂探索性试验旨在评估编码人CYP4V2蛋白(rAAV2/8-hCYP4V2)的重组腺相关病毒血清型2/8载体的安全性和有效性.参与者接受了7.5×1010个rAAV2/8-hCYP4V2载体基因组的单次单侧视网膜下注射。总的来说,报告了73起治疗引起的不良事件，大多数(98.6%)为轻度或中度,被认为与手术或皮质类固醇相关;未观察到与治疗相关的严重不良事件或局部/全身免疫毒性.与基线测量相比，77.8％的治疗眼睛在第180天显示最佳矫正视力（BCVA）的改善，在分析的9只眼睛中平均±标准偏差增加9.0±10.8个字母（p=0.021）。到第365天，80％的治疗眼睛显示BCVA增加，评估的5只眼平均增加11.0±10.6个字母（p=0.125）。重要的是,使用多焦视网膜电图观察到的患者病情改善，显微视野,和视觉功能问卷-25进一步支持治疗的有益效果。我们得出的结论是，该试验中确定的良好安全性和视觉改善鼓励了rAAV2/8-hCYP4V2（命名为ZVS101e）的持续发展。
