Recent advances in regenerative therapy have placed the treatment of many previously incurable eye diseases within arms-reach (Ciulla et al., 2020). Achromatopsia (ACHM) is a severe monogenic heritable retinal disease that disrupts cone function from gestation, leaving patients with complete colour blindness, low acuity, photosensitivity, and nystagmus (Hirji, Aboshiha, et al., 2018). In non-primate animal models of ACHM, retinal gene-replacement therapy has successfully induced cone function in the young (Alexander et al., 2007; Carvalho et al., 2011), but it was yet to be determined if and when these therapies could effectively impact cone-mediated pathways in the human brain. Here we demonstrate in children with ACHM that gene therapy can yield substantial improvement in cone-mediated vision, via cascading effects on signal transmission from retina to cortex. To measure the effects of treatment in children with ACHM (CNGA3- and CNGB3-associated, all aged 10+ years), we developed novel visual stimuli, calibrated to selectively activate cone photoreceptors. We used these in behavioural psychophysics and functional MRI with population receptive field mapping, pre- and post-treatment. The results of treatment, contextualized against data from 12 untreated ACHM patients and 25 normal-sighted, revealed that six months post-therapy, two patients displayed novel responses to our cone-selective stimuli in the visual cortex, with a retinotopic organisation characteristic of normal-sighted individuals, not present in untreated ACHM. This was paired with significant improvement in cone-mediated perception specific to the treated eye, and self-reports of improved vision. Two other patients did not show a post-treatment effect, potentially reflecting individual differences in therapeutic outcome. Together, these data show that gene replacement therapy in humans with ACHM can activate dormant cone pathways despite long-term deprivation. This offers great promise for regenerative therapies, and their ability to trigger the neural plasticity needed to cure congenital vision loss in human patients.

中文翻译：

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色盲基因治疗后锥体功能可塑性的证明

再生疗法的最新进展使许多以前无法治愈的眼部疾病的治疗触手可及（Ciulla 等，2020）。色盲 (ACHM) 是一种严重的单基因遗传性视网膜疾病，从妊娠开始会破坏视锥细胞功能，导致患者出现完全色盲、低视力、光敏性和眼球震颤 (Hirji, Aboshiha, et al., 2018)。在 ACHM 的非灵长类动物模型中，视网膜基因替代疗法已成功诱导年轻人的视锥细胞功能（Alexander 等人，2007 年；Carvalho 等人，2011 年），但尚未确定这些疗法是否以及何时可以有效地影响人脑中锥体介导的通路。在这里，我们在患有 ACHM 的儿童身上证明，基因治疗可以显着改善视锥介导的视力，通过对从视网膜到皮层的信号传输的级联效应。为了测量 ACHM（CNGA3 和 CNGB3 相关，年龄均在 10 岁以上）儿童的治疗效果，我们开发了新型视觉刺激，经过校准以选择性激活视锥光感受器。我们将这些用于行为心理物理学和功能性 MRI 以及人群感受野映射、治疗前和治疗后。根据来自 12 名未经治疗的 ACHM 患者和 25 名视力正常的患者的数据，治疗结果显示，治疗后 6 个月，两名患者对视觉皮层中的视锥选择性刺激表现出新的反应，具有正常的视网膜组织特征- 视力正常的个体，不存在于未经治疗的 ACHM。这与治疗眼睛特有的视锥介导感知的显着改善相结合，以及视力改善的自我报告。另外两名患者没有表现出治疗后的效果，这可能反映了治疗结果的个体差异。总之，这些数据表明，尽管长期剥夺，人类 ACHM 的基因替代疗法可以激活休眠锥体通路。这为再生疗法及其触发治疗人类患者先天性视力丧失所需的神经可塑性的能力提供了广阔的前景。