Gene therapy holds promise for treatment of inherited retinal dystrophies, a group of rare genetic disorders characterized by severe loss of vision. Here, we report up to 3-year pre-specified interim safety and efficacy results of an open-label first-in-human dose-escalation phase 1/2 gene therapy clinical trial in 12 patients with retinal dystrophy caused by biallelic mutations in the retinaldehyde-binding protein 1 (RLBP1) gene of the visual cycle. The primary endpoints were systemic and ocular safety and recovery of dark adaptation. Secondary endpoints included microperimetry, visual field sensitivity, dominant eye test and patient-reported outcomes. Subretinal delivery of an adeno-associated viral vector (AAV8-RLBP1) was well tolerated with dose-dependent intraocular inflammation which responded to corticosteroid treatment, and focal atrophy of the retinal pigment epithelium as the dose limiting toxicity. Dark adaptation kinetics, the primary efficacy endpoint, improved significantly in all dose-cohorts. Treatment with AAV8-RLBP1 resulted in the resolution of disease-related retinal deposits, suggestive of successful restoration of the visual cycle. In conclusion, to date, AAV8-RLBP1 has shown preliminary safety and efficacy in patients with RLBP1-associated retinal dystrophy. Trial number: NCT03374657.

基因疗法有望治疗遗传性视网膜营养不良，这是一组以严重视力丧失为特征的罕见遗传疾病。在这里，我们报告了一项开放标签首次人体剂量递增 1/2 期基因治疗临床试验的长达 3 年预先指定的中期安全性和有效性结果，该试验在 12 名由视黄醛结合蛋白 1 （RLBP1） 基因的双等位基因突变引起的视网膜营养不良患者中视觉周期。主要终点是全身和眼部安全性以及暗适应的恢复。次要终点包括显微视野计、视野敏感性、优势眼试验和患者报告的结局。腺相关病毒载体 （AAV8-RLBP1） 的视网膜下递送耐受性良好，对皮质类固醇治疗有反应的剂量依赖性眼内炎症，以及视网膜色素上皮的局灶性萎缩作为剂量限制性毒性。暗适应动力学是主要疗效终点，在所有剂量队列中均显著改善。AAV8-RLBP1 治疗导致疾病相关视网膜沉积物消退，表明视觉周期成功恢复。总之，迄今为止，AAV8-RLBP1 已在 RLBP1 相关视网膜营养不良患者中显示出初步的安全性和有效性。试验编号：NCT03374657。