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Eberherr, A.C. ; Maaske, A. ; Wolf, C. ; Giesert, F. ; Berutti, R. ; Rusha, E. ; Pertek, A. ; Kastlmeier, M.T. ; Voss, C. ; Plummer, M. ; Sayed, A. ; Graf, E. ; Effner, R. ; Volz, T.* ; Drukker, M. ; Strom, T.M. ; Meitinger, T. ; Stöger, T. ; Buyx, A.M.* ; Hagl, B. ; Renner, E.D.

Rescue of STAT3 function in hyper-IgE syndrome using adenine base editing.

CRISPR J. 4, 178-190 (2021)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2573-1599
e-ISSN 2573-1602
Journal The CRISPR Journal
Quellenangaben Volume: 4, Issue: 2, Pages: 178-190 Article Number: , Supplement: ,
Publisher Mary Ann Liebert
Publishing Place 140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Environmental Medicine (IEM)
Institute of Developmental Genetics (IDG)
Institute of Neurogenomics (ING)
Institute of Lung Health and Immunity (LHI)
Institute of Human Genetics (IHG)
Institute of Stem Cell Research (ISF)
POF-Topic(s) 30202 - Environmental Health
30204 - Cell Programming and Repair
30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Allergy

Genetics and Epidemiology
Lung Research
Stem Cell and Neuroscience
PSP Element(s) G-503400-002
G-508200-029
G-503400-003
G-500500-001
G-503292-001
G-505000-001
G-500700-001
G-503400-001
G-500800-001
G-552400-001
Grants Helmholtz Translational Clinical Project
Helmholtz-Future topic "Immunology and Inflammation''
German Research Foundation
Fritz Bender Stiftung
DOI 10.1089/crispr.2020.0111
WOS ID WOS:000642276500006
Scopus ID 85104807802
PubMed ID 33876960
Erfassungsdatum 2021-06-08
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