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.
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.
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.