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Updated: Jun 6, 2025
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Published on: March 5, 2017
Targeting the IDH1 R132H mutation in gliomas by CRISPR/Cas precision base editing
Remi Weber1, Flavio Vasella2,1, Artsiom Klimko1
1Laboratory of Molecular Neuro-Oncology, Department of Neurology, Clinical Neuroscience Centre, University Hospital and University of Zurich, Zurich, Switzerland.
Background:
Gliomas, the most frequent malignant primary brain tumors, lack curative treatments. Understanding glioma-specific molecular alterations is crucial to develop novel therapies. Among them, the biological consequences of the isocitrate dehydrogenase 1 gene mutation (IDH1 R132H) remain inconclusive despite its early occurrence and widespread expression.
Methods:
We thus employed CRISPR/Cas adenine base editors, which allow precise base pair alterations with minimal undesirable effects, to correct the IDH1 R132H mutation.
Results:
Successful correction of the IDH1 R132H mutation in primary patient-derived cell models led to reduced IDH1 R132H protein levels and decreased production of 2-hydroxyglutarate, but increased proliferation. A dual adeno-associated virus split intein system was used to successfully deliver the base editor in vitro and in vivo.
Conclusions:
Taken together, our study provides a strategy for a precise genetic intervention to target the IDH1 R132H mutation, enabling the development of accurate models to study its impact on glioma biology and serving as a framework for an in vivo gene therapy.
