Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

内质网 (ER) 应激和未折叠蛋白反应 (UPR) 信号传导促进许多人类疾病的病理。UPR 调节因子激活转录因子 6 (ATF6)的功能丧失变异会导致严重的先天性视力丧失疾病，例如色盲，其病理机制尚不清楚。为了研究这一点，我们从全色盲患者诱导的携带ATF6疾病变异的多能干细胞和基因编辑的ATF6 null hESC 中生成了视网膜类器官。我们发现全色盲患者和ATF6缺失的视网膜类器官无法形成视锥细胞结构，同时视锥细胞光转导基因表达缺失，而视杆细胞光感受器发育正常。携带ATF6变体的全色盲患者的自适应光学视网膜成像也显示，视锥细胞内/外节段结构不存在，但保留了杆状结构，反映了在我们的视网膜类器官中观察到的视锥细胞形成缺陷。这些结果证实 ATF6 对于人体锥体发育至关重要。有趣的是，我们发现选择性小分子 ATF6 信号激动剂可以恢复一些ATF6致病变异的转录活性，并刺激携带这些变异的患者视网膜类器官中的视锥细胞生长和基因表达。这些发现支持 ATF6 通路的药理学靶向可以促进人类视锥细胞发育，并且应该进一步探索用于致盲性视网膜疾病。