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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.
Insights
Researchers used CRISPR/Cas base editing to correct the isocitrate dehydrogenase 1 gene mutation (IDH1R132H) in glioma cells. This genetic intervention offers a new strategy for understanding and potentially treating this common brain tumor.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Gene Editing
Background:
- Gliomas are the most common malignant brain tumors, lacking effective curative treatments.
- Understanding molecular alterations, like the IDH1R132H mutation, is key for developing new glioma therapies.
- The biological impact of the IDH1R132H mutation is not fully understood despite its prevalence.
Purpose of the Study:
- To precisely correct the IDH1R132H mutation using CRISPR/Cas adenine base editors.
- To investigate the effects of correcting this mutation on glioma cell biology.
- To establish a gene therapy framework for targeting IDH1R132H in vivo.
Main Methods:
- Utilized CRISPR/Cas adenine base editors for precise gene correction.
- Employed a dual adeno-associated virus split intein system for in vitro and in vivo delivery.
- Studied primary patient-derived cell models to assess mutation correction outcomes.
Main Results:
- Successfully corrected the IDH1R132H mutation in patient-derived glioma models.
- Observed reduced IDH1R132H protein levels and 2-hydroxyglutarate production post-correction.
- Reported increased cell proliferation following the correction of the IDH1R132H mutation.
Conclusions:
- Developed a precise genetic intervention strategy targeting the IDH1R132H mutation.
- Enabled the creation of accurate models to study the impact of IDH1R132H on glioma.
- Provided a framework for potential in vivo gene therapy for IDH1-mutated gliomas.
