Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing

Eberherr AC, Maaske A, Wolf C, Giesert F, Berutti R, Rusha E, Pertek A, Kastlmeier MT, Voss C, Plummer M, Sayed A, Graf E, Effner R, Volz T, Drukker M, Strom TM, Meitinger T, Stoeger T, Buyx AM, Hagl B, Renner ED (2021)

Publication Type: Journal article

Publication year: 2021

Journal

CRISPR Journal Mary Ann Liebert Inc. Publishers

Book Volume: 4

Pages Range: 178-190

Journal Issue: 2

DOI: 10.1089/crispr.2020.0111

Abstract

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.

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Eberherr, A.C., Maaske, A., Wolf, C., Giesert, F., Berutti, R., Rusha, E.,... Renner, E.D. (2021). Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing. CRISPR Journal, 4(2), 178-190. https://doi.org/10.1089/crispr.2020.0111

MLA:

Eberherr, Andreas C., et al. "Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing." CRISPR Journal 4.2 (2021): 178-190.

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