# Targeting IDH mutations to improve seizure control in glioma patients

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $360,341

## Abstract

PROJECT SUMMARY
Diffusely infiltrative glioma is the most common primary brain tumor in adults. Most glioma patients experience
at least one seizure during the course of their disease, and over 30% suffer from repeated seizures, known as
tumor-associated epilepsy (TAE). Current front-line treatment for TAE is levetiracetam (LEV) (a.k.a. Keppra®),
but this fails to control seizures in over 50% of patients. Such patients then require more powerful second-line
antiepileptic drugs that often have greater side effects. TAE is more common in World Health Organization
(WHO) grade II-III gliomas than in grade IV glioblastomas, but the reason for this is not clear. The vast majority
of grade II-III gliomas contain mutations in isocitrate dehydrogenases 1 and 2 (collectively “IDHmut”), which lead
to the production and release of large amounts of D-2-hydroxyglutarate (D2HG). D2HG bears a great deal of
structural similarity to glutamate, an excitatory neurotransmitter that binds to N-methyl-D-aspartate receptor
(NMDAR) on neurons. Our data show that D2HG increases in vitro neuronal membrane depolarization and
neuronal network activity, and that this can be completely blocked by an NMDA receptor (NMDAR) antagonist.
We also found that IDHmut glioma increases seizure activity in engrafted mice compared to IDHwt glioma, and
that this is greatly reduced by treatment with IDHmut enzyme inhibitor. Finally, we found that IDHmut gliomas are
much more likely to cause seizures compared to IDHwt gliomas. This is the first direct evidence of a mechanistic
link between IDHmut and seizures; therefore, our hypothesis is that D2HG contributes to an increased
incidence of seizures in patients with IDHmut gliomas, and that new targeted therapeutic strategies can
decrease seizures in these patients. In Aim 1, we will explore the mechanisms by which D2HG triggers
neuronal depolarization and increased neuronal network activity. Our two main hypotheses are: (i) D2HG directly
stimulates NMDA receptors; (ii) D2HG inhibits glutamate reuptake transporters that normally prevent the
pathologic accumulation of glutamate in the synaptic cleft. We will use patch clamping and multi-electrode arrays
to study the effects of D2HG on the electrical activity of cultured mouse cortical neurons, as well as on mouse
brain slices. In Aim 2, we will explore the effects of IDHmut glioma on the surrounding nonneoplastic tissue in
vivo, focusing on changes that are characteristic of epilepsy, including neuronal loss, NMDAR downregulation,
oxidative stress, inflammation, hippocampal damage, and altered mouse behavior. Results will be validated in
patient-derived IDHwt and IDHmut gliomas. In Aim 3, we will compare the anti-seizure effects of two next-
generation IDHmut inhibitors, AG-120 and AG-881, as well as memantine, an NMDAR antagonist that is already
used to treat Alzheimer’s Disease. Each of these drugs will be tested as monotherapy and in combination with
LEV. Successful completion of these Aims w...

## Key facts

- **NIH application ID:** 10840901
- **Project number:** 5R01NS118039-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Craig Michael Horbinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,341
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840901

## Citation

> US National Institutes of Health, RePORTER application 10840901, Targeting IDH mutations to improve seizure control in glioma patients (5R01NS118039-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10840901. Licensed CC0.

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