May 30, 2024 03:01:13

Potential Therapeutic Target Identified for Genetic Form of Epilepsy

Developmental and epileptic encephalopathies, rare forms of epilepsy beginning in childhood, lack targeted treatments. Researchers from the Francis Crick Institute, UCL, and MSD have identified a potential treatment target for a hereditary epilepsy form, CDKL5-deficient disorder (CDD).

CDKL5 is a gene producing the CDKL5 enzyme that phosphorylates proteins. The study utilized mice without the Cdkl5 gene and employed phosphoproteomics to identify proteins targeted by the CDKL5 enzyme. CDD is marked by seizures and delayed development, and current treatments involve generic antiepileptic drugs.

The study pinpointed a calcium channel, Cav2.3, as a target. While crucial for normal nervous system function, an excess of calcium entering cells can lead to seizures. The researchers found that CDKL5 is essential for limiting calcium entry into cells by phosphorylating Cav2.3, and when lacking CDKL5, these channels exhibited prolonged activity.

Nerve cells derived from the stem cells of individuals with CDD showed reduced phosphorylation of Cav2.3, indicating potential alterations in humans as well as mice. Mutations in Cav2.3 known to increase channel activity are linked to severe early-onset epilepsy. The findings suggest that inhibiting Cav2.3 could alleviate symptoms like seizures in both CDD and related conditions.

Sila Ultanir, Senior Group Leader at the Crick, highlighted the need for drugs targeting CDD’s biological nature, expressing hope that inhibiting Cav2.3 could pave the way for targeted treatments. Marisol Sampedro-Castaneda, the study’s first author, emphasized the potential wider application of Cav2.3 inhibitors for various epilepsy types.

MSD, in collaboration with the Crick and UCL, sees this research as contributing to scientific progress in understanding developmental epileptic encephalopathies, addressing a significant area of unmet medical need.