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Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing
Andreas C Eberherr1,2, Andre Maaske1,2, Christine Wolf1,2
1Translational Immunology in Environmental Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; Technical University of Munich, Munich, Germany.
The CRISPR Journal
|April 20, 2021
Summary
Adenine base editors successfully corrected the STAT3 mutation causing STAT3-hyper IgE syndrome (STAT3-HIES). This gene correction approach shows promise for treating STAT3-HIES by restoring STAT3 signaling and enabling functional rescue in patient cells.
Area of Science:
- Genetics and Genomics
- Immunology
- Gene Therapy
Background:
- STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency characterized by severe lung disease.
- A common cause of STAT3-HIES is a heterozygous mutation in the STAT3 gene (c.1144C>T/p.R382W).
Purpose of the Study:
- To evaluate the efficacy of CRISPR-Cas9-mediated adenine base editors (ABEs) for correcting the STAT3 p.R382W mutation.
- To assess the functional consequences of gene correction in patient-derived cells.
Main Methods:
- Adenine base editors (ABEs) were applied to correct the STAT3 p.R382W mutation in patient fibroblasts and induced pluripotent stem cells (iPSCs).
- Correction efficiency and off-target effects were assessed using whole-genome and high-throughput sequencing.
- Functional rescue of STAT3 signaling was evaluated by measuring STAT3 DNA-binding activity and target gene expression (CCL2, SOCS3).
- Corrected iPSCs were differentiated into alveolar organoids.
Main Results:
- ABE treatment achieved a STAT3 gene correction efficiency of approximately 29% in fibroblasts and 30% in iPSCs, with no detectable off-target mutations.
- Corrected cells exhibited restored STAT3 signaling, evidenced by increased STAT3 DNA-binding activity and target gene expression.
- Patient-derived iPSCs maintained plasticity after differentiation into alveolar organoids.
Conclusions:
- ABE-based gene correction is a viable strategy for addressing the genetic defect in STAT3-HIES.
- This approach offers potential as a causative treatment for STAT3-HIES, restoring cellular function and potentially mitigating disease progression.
