Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing
车站3
基因
生物
癌症研究
遗传学
作者
Andreas C. Eberherr,André Maaske,Christine Wolf,Florian Giesert,Riccardo Berutti,Ejona Rusha,Anna Pertek,Miriam T. Kastlmeier,Carola Voss,Michelle D. Plummer,Amina Sayed,Elisabeth Graf,Renate Effner,Thomas Volz,Micha Drukker,Tim M. Strom,Thomas Meitinger,Tobias Stoeger,Alena Buyx,Beate Hagl,Ellen D. Renner
出处
期刊:The CRISPR journal [Mary Ann Liebert] 日期:2021-04-01卷期号:4 (2): 178-190被引量:11
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.