Jia Ruixuan, Meng Xiang, Chen Shaohong, Zhang Fan, Du Juan, Liu Xiaozhen, Yang Liping
Key Laboratory of Vision Loss and Restoration, Department of Ophthalmology, Ministry of Education, Peking University Third Hospital, Beijing, People's Republic of China.
Beijing Chinagene Corporation Ltd, Beijing, People's Republic of China.
Hum Mol Genet. 2023 Jan 1;32(1):122-138. doi: 10.1093/hmg/ddac181.
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degenerative disease characterized by yellow-white crystal deposits in the posterior pole, degeneration of the retinal pigment epithelium (RPE), and sclerosis of the choroid. Mutations in the cytochrome P450 4V2 gene (CYP4V2) cause BCD, which is associated with lipid metabolic disruption. The use of gene-replacement therapy in BCD has been hampered by the lack of disease models. To advance CYP4V2 gene-replacement therapy, we generated BCD patient-specific induced pluripotent stem cell (iPSC)-RPE cells and Cyp4v3 knockout (KO) mice as disease models and AAV2/8-CAG-CYP4V2 as treatment vectors. We demonstrated that after adeno-associated virus (AAV)-mediated CYP4V2 gene-replacement therapy BCD-iPSC-RPE cells presented restored cell survival and reduced lipid droplets accumulation; restoration of vision in Cyp4v3 KO mice was revealed by elevated electroretinogram amplitude and ameliorated RPE degeneration. These results suggest that AAV-mediated gene-replacement therapy in BCD patients is a promising strategy.
比埃蒂结晶性角膜视网膜营养不良（BCD）是一种常染色体隐性视网膜退行性疾病，其特征为后极部出现黄白色晶体沉积、视网膜色素上皮（RPE）变性以及脉络膜硬化。细胞色素P450 4V2基因（CYP4V2）突变导致BCD，这与脂质代谢紊乱有关。由于缺乏疾病模型，BCD的基因替代疗法进展受阻。为推动CYP4V2基因替代疗法的发展，我们生成了BCD患者特异性诱导多能干细胞（iPSC）-RPE细胞和Cyp4v3基因敲除（KO）小鼠作为疾病模型，并使用AAV2/8-CAG-CYP4V2作为治疗载体。我们证明，在腺相关病毒（AAV）介导的CYP4V2基因替代疗法后，BCD-iPSC-RPE细胞的细胞存活率得以恢复，脂滴积累减少；通过视网膜电图振幅升高和RPE变性改善，显示Cyp4v3 KO小鼠的视力得到恢复。这些结果表明，AAV介导的BCD患者基因替代疗法是一种有前景的策略。
