STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.

中文翻译：

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使用腺嘌呤碱基编辑挽救高 IgE 综合征中的 STAT3 功能

STAT3-高 IgE 综合征 (STAT3-HIES) 是一种原发性免疫缺陷，表现为破坏性肺病和其他症状。CRISPR-Cas9 介导的腺嘌呤碱基编辑器 (ABE) 有可能纠正导致杂合STAT3突变的最常见 STAT3-HIES 之一（c.1144C>T/p.R382W）。作为概念验证，我们成功地应用 ABE 来纠正STAT3患者成纤维细胞和诱导多能干细胞 (iPSC) 中的 p.R382W。经处理的原代 STAT3-HIES 患者成纤维细胞显示出 29% ± 7% 的校正效率，没有通过全基因组和高通量测序评估的可检测脱靶效应。与未经治疗的患者成纤维细胞相比，校正后的单细胞克隆显示出 STAT3 信号的功能性拯救，STAT3 DNA 结合活性和CCL2和SOCS3 的靶基因表达显着增加。患者来源的 iPSC 以 30% ± 6% 的效率得到校正，并分化为肺泡类器官，在处理过的细胞中显示出保留的可塑性。总之，我们的结果支持基于 ABE 的基因校正作为 STAT3-HIES 的潜在病因治疗。