NMDAR; NMDA receptor NR2A subtype
Human genetic and cell
culture studies suggest modulating NMDARs could be useful for treating
certain forms of epilepsy. Exome sequencing of patients with epilepsy by
three independent teams found de novo and inherited mutations in GRIN2A
in up to 20% of patients who have idiopathic focal epilepsy, acquired
epileptic aphasia, continuous spike and waves during slow-wave sleep
syndrome, benign epilepsy with centrotemporal spikes and other variants of
epilepsy-aphasia syndromes. In cell culture, several disease-associated GRIN2A
mutations caused higher NMDAR ion channel activity than wild-type GRIN2A.
Next steps include screening for compounds that normalize the function of
GRIN2A with disease-associated mutations.
Pharmaceuticals Inc. has GRIN2A-selective NMDAR modulators
in preclinical development for schizophrenia, depression and autism.
Insero Health Inc. has the NMDAR modulator huperzine A
(INS001) in Phase I testing
to treat drug-resistant epilepsy.
At least 20 companies have nonselective NMDAR modulators in development or on
the market for various neurological indications.
Published online Sept. 12, 2013
Findings from all three
studies unpatented; licensing status not applicable
Lesca, G. et al. Nat.
Genet.; published online Aug. 11, 2013;
Contact: Pierre Szepetowski, Aix-Marseille University,
Carvill, G.L. et al. Nat. Genet.; published online Aug. 11, 2013;
Contact: Heather C. Mefford, University of Washington,
Contact: Ingrid E. Scheffer, The University of Melbourne,
Melbourne, Victoria, Australia
Lemke, J.R. et al. Nat. Genet.; published online Aug. 11, 2013;
Contact: Sarah von Spiczak, Kiel University, Kiel, Germany
Contact: Holger Lerche, University of Tuebingen, Tuebingen,