Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa,Molecular Therapy

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Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa
Molecular Therapy ( IF 12.1 ) Pub Date : 2022-06-10 , DOI: 10.1016/j.ymthe.2022.06.005
Sung-Ah Hong ₁ , Song-Ee Kim ₂ , A-Young Lee ₂ , Gue-Ho Hwang ₃ , Jong Hoon Kim ₂ , Hiroaki Iwata ₄ , Soo-Chan Kim ₅ , Sangsu Bae ₆ , Sang Eun Lee ₂

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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for gene editing to treat RDEB.

中文翻译：

隐性营养不良性大疱性表皮松解症 COL7A1 突变的治疗性碱基编辑和引物编辑

隐性营养不良性大疱性表皮松解症 (RDEB) 是一种严重的皮肤脆弱性疾病，由基因功能丧失突变引起，该基因编码 VII 型胶原蛋白 (C7)，一种在皮肤粘附中发挥作用的蛋白质。从 36 名韩国 RDEB 患者中，我们总共鉴定出 69 种致病突变（40 种无复发变异），包括点突变（72.5%）和插入/缺失突变（27.5%）。对于来自两名患者（Pat1 和 Pat2）的成纤维细胞，我们应用腺嘌呤碱基编辑器 (ABE) 来纠正 Pat1 衍生的原代成纤维细胞中的致病性突变或绕过过早终止密码子。为了扩大靶向范围，我们还利用初等编辑器 (PE) 来纠正 Pat1 和 Pat2 衍生的成纤维细胞中的突变。最终，我们发现将经过编辑的患者来源的皮肤等同物（即来自 RDEB 患者的 RDEB 角质形成细胞和 PE 校正的 RDEB 成纤维细胞）转移到免疫缺陷小鼠的皮肤中，导致 C7 沉积并在真皮-表皮连接处锚定原纤维形成。表明碱基编辑和引物编辑可能是基因编辑治疗 RDEB 的可行策略。

更新日期：2022-06-10

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