CURE Discovery: Understanding and Treating NMDA Receptor-Associated Epilepsy
Key Takeaways:
- Researchers are studying whether off-label treatment with certain FDA-approved drugs can improve seizure control for individuals whose epilepsy is caused by over-activation of NMDA-R.
- The CURE-funded team is researching previously unstudied mutations in GRIN genes and using this information to determine who might benefit from off-label treatment with NMDA-R blockers.
- Interested families with a genetic diagnosis of a GRIN mutation and epilepsy can enroll in this important study. Contact Jenifer Sargent at [email protected] for more information.
Deep Dive:
Can off-label use of certain FDA-approved drugs which reduce NMDA-R function improve seizure control in patients with epilepsy caused by over-activation of NMDA-R? That is the question a CURE-funded study by Dr. Stephen Traynelis at Emory University and his team aims to answer.
Dr. Traynelis and his collaborators, Drs. Sooky Koh, Ann Poduri, and Tim Benke, will assess if epilepsy caused by over-activation of a protein in the brain, called the N-methyl-D-aspartate receptor (NMDA-R), can be improved when patients with GRIN mutations are treated off-label by their clinicians with certain FDA-approved NMDA-R blockers. They also hope to determine if treatment with these drugs has any positive effects on developmental progress in addition to improved seizure control.
NMDA-R is an essential component of electrical signaling in the brain and is made from proteins encoded by the GRIN family of genes.1 Because GRIN genes provide the blueprint for NMDA-R, mutations in these genes can impact how the NMDA-R works. Not all of these mutations cause over-activation of the NMDA-R, so in the first part of this project, the researchers are investigating each human GRIN mutation that has not been studied before by re-creating them in the laboratory and evaluating how they affect NMDA-R activity. This information will then be used to determine who might benefit from off-label treatment with drugs that reduce NMDA-R function.
People with GRIN variants that data suggest produce a strong over-activation of the NMDA-R might be candidates for treatment by their physician with NMDA-R blockers. Those with GRIN variants that reduce activity of the NMDA-R or produce complex actions which are difficult to clearly categorize would not be expected to benefit from treatment.
The investigators have created a registry where families affected by GRIN mutations can sign up to participate. The registry collects medical history data and records that are stored without any identifying information to protect the privacy of each participant. Following analysis of a patient’s mutation status, a report is shared with their clinician who will judge whether it is in the patient’s best interest to be considered for off-label treatment. Treatment could then be offered to the family and is based on treatment guidelines Dr. Traynelis and his collaborators have developed.
The team will follow up with a retrospective analysis of treatment efficacy. That is, the investigators will go back and analyze medical records, EEG data, seizure history, and other relevant data for people who received off-label treatment from their physicians to understand how well the treatment worked. This data will also allow an assessment of whether particular GRIN mutations may benefit more from the treatment than others.
This study is expected to provide data for a clinical trial that could lead to new therapies for these difficult to treat epilepsies. In a previously published study, the investigators treated a child with early-onset epileptic encephalopathy associated with a mutation in GRIN2A with the drug memantine and found a substantial reduction in his seizure burden after treatment for a year.2 Additional studies provided more mixed results, creating a need to better understand the utility of this approach.
The team is looking to enroll additional families in this important study. If you or anyone you know with a genetic diagnosis of a GRIN mutation and epilepsy are interested in participating, please contact Jenifer Sargent at [email protected] to learn more about the study.
1 Hansen KB, Feng Y et. al., J Gen Physiol. 2018 Aug 6; 150(8): 1081–1105
2 Pierson TM, Yuan H et. al., Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198
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