Yang Paul, Birch David, Lauer Andreas, Sisk Robert, Anand Rajiv, Pennesi Mark E, Iannaccone Alessandro, Yaghy Antonio, Scaria Abraham, Jung Jung Ah, Curtiss Darin, Waheed Nadia K
From the Paul H. Casey Ophthalmic Genetics Division (P.Y., A.L., M.E.P.), Casey Eye Institute, Oregon Health & Science University, Oregon, Portland, USA.
Retina Foundation of the Southwest (D.B., M.E.P.), Dallas, Texas, USA.
Am J Ophthalmol. 2025 Mar;271:268-285. doi: 10.1016/j.ajo.2024.11.021. Epub 2024 Dec 4.
To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP).
Phase 1/2, open-label, dose-escalation study.
Setting: Four centers in the United States. Patient or Study Population: Twenty-nine males with XLRP and confirmed pathogenic RPGR variants. Mean age was 31.6 years (range 15-55).
Subretinal injection of AGTC-501 at doses ranging from 2.48 × 10 to 1.99 × 10 vg/eye administered in one eye per participant. Subretinal injection sites initially targeted the peripheral retina and then transitioned to the macula with successive cohorts.
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory parameters, and immunological responses. Efficacy was evaluated by mesopic microperimetry mean sensitivity.
All 29 participants experienced ≥1 TEAE. Eleven (38%) experienced ≥1 grade 3 TEAE. Six (21%) experienced ≥1 ocular SAE related to AGTC-501, including retinal detachment (n = 4), subcapsular cataract (n = 1), and glaucoma (n = 1). Two (6.9%) experienced non-ocular treatment-emergent SAEs. Immunological findings did not indicate safety concerns. Three of 4 participants at the highest dose exhibited concerning retinal pigment epithelial changes. Half the participants at the highest tolerated dose (6.8 × 10vg/eye) maintained ≥7 dB improvement in ≥5 loci at 24 months.
Subretinal AGTC-501 was generally well-tolerated. Despite all participants experiencing at least one TEAE, most of these events were mild in nature, exhibited complete resolution, and were associated with the subretinal injection procedure itself rather than the study agent. The highest dose exhibited an unfavorable risk-benefit profile due to the development of RPE changes. Although this group had the highest improvement in retinal sensitivity, our team has decided not to continue this dose in future clinical trials. Preliminary efficacy was observed at the maximum tolerated dose. Further studies are warranted to assess long-term safety and efficacy of AGTC-501 for XLRP treatment.
评估使用AGTC - 501（rAAV2tYF - GRK1 - RPGR）对患有X连锁视网膜色素变性（XLRP）的男性参与者进行视网膜下基因治疗的安全性和有效性。
1/2期、开放标签、剂量递增研究。
地点：美国的四个中心。患者或研究人群：29名患有XLRP且确诊为致病性RPGR变异的男性。平均年龄为31.6岁（范围15 - 55岁）。
对每位参与者的一只眼睛进行视网膜下注射AGTC - 501，剂量范围为2.48×10至1.99×10病毒基因组/眼。视网膜下注射部位最初靶向周边视网膜，随后随着连续队列转移至黄斑区。
治疗中出现的不良事件（TEAE）、严重不良事件（SAE）、实验室参数和免疫反应。通过中亮度微视野平均敏感度评估疗效。
所有29名参与者均经历了≥1次TEAE。11名（38%）经历了≥1次3级TEAE。6名（21%）经历了≥1次与AGTC - 501相关的眼部SAE，包括视网膜脱离（n = 4）、后囊下白内障（n = 1）和青光眼（n = 1）。2名（6.9%）经历了非眼部治疗中出现的SAE。免疫结果未表明存在安全问题。最高剂量组的4名参与者中有3名出现了令人担忧的视网膜色素上皮变化。在最高耐受剂量（6.8×10病毒基因组/眼）下，一半的参与者在24个月时在≥5个位点维持了≥7 dB的改善。
视网膜下注射AGTC - 501总体耐受性良好。尽管所有参与者都至少经历了一次TEAE，但这些事件大多性质轻微，表现为完全缓解，且与视网膜下注射操作本身而非研究药物相关。由于出现了视网膜色素上皮变化，最高剂量组呈现出不利的风险效益比。尽管该组视网膜敏感度改善最大，但我们团队决定在未来临床试验中不再继续使用该剂量。在最大耐受剂量下观察到了初步疗效。有必要进一步研究评估AGTC - 501治疗XLRP的长期安全性和有效性。
