人源性 CRB1KO 和 CRB1KOCRB2+/- 视网膜类器官的表征和 AAV 介导的 CRB 基因增强,Molecular Therapy - Methods & Clinical Development

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人源性 CRB1KO 和 CRB1KOCRB2+/- 视网膜类器官的表征和 AAV 介导的 CRB 基因增强
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2023-10-10 , DOI: 10.1016/j.omtm.2023.101128
Nanda Boon ₁ , Xuefei Lu ₁ , Charlotte A Andriessen ₁ , Michaela Orlovà ₁ , Peter M J Quinn ₁ , Camiel J F Boon _{1,

2} , Jan Wijnholds _{1,

3}

Affiliation

大多数携带突变的患者在幼儿时会出现早发性视网膜色素变性，或在新生儿时会出现莱伯先天性黑蒙。相关视网膜病表型变异的原因尚不清楚，但可能与 Müller 胶质细胞和感光细胞中 CRB1 和 CRB2 蛋白水平的差异有关。此处，分化第210天的视网膜类器官显示，连续感光细胞核的数量显着减少，而外界膜上方的感光细胞核的数量显着增加。这种具有外视网膜异常的表型类似于患者来源的视网膜类器官和/或突变小鼠视网膜疾病模型。由于 Müller 胶质细胞完全丧失了 CRB1，视网膜类器官形成了额外的视网膜内表型，这表明 CRB1 在神经元细胞类型的正确定位中发挥着重要作用。在类器官发育的早期和晚期阶段探索了腺相关病毒（AAV）转导。此外，AAV 介导的 AAV.h 基因增强疗法改善了视网膜类器官中的外视网膜表型。总而言之，这些数据为未来针对相关视网膜营养不良患者的基因治疗方法提供了重要信息。

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Characterization and AAV-mediated CRB gene augmentation in human-derived CRB1KO and CRB1KOCRB2+/− retinal organoids

The majority of patients with mutations in develop either early-onset retinitis pigmentosa as young children or Leber congenital amaurosis as newborns. The cause for the phenotypic variability in -associated retinopathies is unknown, but might be linked to differences in CRB1 and CRB2 protein levels in Müller glial cells and photoreceptor cells. Here, and differentiation day 210 retinal organoids showed a significant decrease in the number of photoreceptor nuclei in a row and a significant increase in the number of photoreceptor cell nuclei above the outer limiting membrane. This phenotype with outer retinal abnormalities is similar to patient-derived retinal organoids and or mutant mouse retinal disease models. The and retinal organoids develop an additional inner retinal phenotype due to the complete loss of CRB1 from Müller glial cells, suggesting an essential role for CRB1 in proper localization of neuronal cell types. Adeno-associated viral (AAV) transduction was explored at early and late stages of organoid development. Moreover, AAV-mediated gene augmentation therapy with AAV.h improved the outer retinal phenotype in retinal organoids. Altogether, these data provide essential information for future gene therapy approaches for patients with -associated retinal dystrophies.

更新日期：2023-10-10

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