Targeting the mutation in gliomas by CRISPR/Cas precision base editing.

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 ( ) 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 mutation.

RESULTS

Successful correction of the mutation in primary patient-derived cell models led to reduced 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 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.