X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.

X 连锁视网膜劈裂症 (XLRS) 是一种早发性经视网膜营养不良，通常具有明显的黄斑成分，影响男性，并且由于 X 连锁隐性遗传，通常不影响杂合子女性。它是由功能丧失RS1引起的X染色体上的基因突变。XLRS 从年轻时就导致双侧视力下降，在临床检查和眼相干断层扫描 (OCT) 中，神经感觉视网膜在外丛状 (OPL) 和内核层 (INL) 中显示中央凹-黄斑囊性劈裂腔。XLRS 表现在婴儿期和学龄期之间，具有可变的表型表现，并且没有可靠的基因型-表型相关性。INL 紊乱破坏了从光感受器到双极细胞的突触信号传输，这会不成比例地减少视网膜电图 (ERG) 双极 b 波与光感受器 a 波的变化。RS1基因表达主要定位于光感受器和 INL 双极神经元，并且 RS1 蛋白被认为在正常视网膜发育过程中以及随后对视网膜结构的维持中起关键的细胞粘附作用。创建了几个具有突变 RS1 的独立 XLRS 小鼠模型，这些模型概括了人类 XLRS 疾病的特征，具有 OPL-INL 劈裂腔、突变模型中的早发和可变表型，并降低了 ERG b 波与 a 波振幅比。XLRS 小鼠的忠实表型有助于描述疾病的病理生理学。将 AAV8- RS1递送至 XLRS 小鼠视网膜在 RS1 启动子控制下的构建恢复了视网膜结构和突触功能（随着 b 波振幅的增加）。它还改善了分裂诱导的炎性小胶质细胞表型，使其处于免疫静止状态。结果表明，XLRS 基因治疗可以产生治疗益处，以保护视网膜的形态和功能，特别是在视网膜变性变得不可逆之前的早期进行干预时。一项 I/IIa 期单中心、开放标签、三剂量递增临床试验报告了玻璃体内施用 AAV8- RS1的合适安全性和耐受性概况XLRS 参与者的基因替代疗法。给药后发生与剂量相关的眼部炎症，但通过局部和口服皮质类固醇解决。针对 AAV8 的全身抗体以剂量依赖性方式增加，但没有观察到针对 RS1 蛋白的抗体。一名参与者的视网膜腔暂时关闭。基因传递方法的技术创新和进一步减少免疫反应的策略有望提高载体的治疗效果和基因治疗方法的最终成功。