Identification of a new therapeutic target for a rare type of childhood epilepsy

Researchers from the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy.

Developmental and epileptic encephalopathies are rare types of epilepsy that begin in early childhood. One of the most common types of genetic epilepsy, CDKL5 deficiency disorder (CDD), causes seizures and developmental disorders. Children are currently treated with generic antiepileptic drugs, as there are no medications targeting this condition yet.

CDD involves the loss of function of a gene producing the enzyme CDKL5, which phosphorylates proteins, meaning it adds an extra phosphate molecule to change their function. Until now, researchers weren’t sure how genetic mutations in CDKL5 caused CDD.

Thanks to their research, published in Natural communicationsThe researchers looked at mice lacking the Cdkl5 gene and used a technique called phosphoproteomics to look for target proteins of the CDKL5 enzyme.

They identified a calcium channel, Cav2.3, as the target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to transmit electrical signals. This is necessary for the nervous system to function properly, but too much calcium entering cells can lead to overexcitability and seizures.

The researchers then recorded the calcium channels to see what happened when they were not phosphorylated by CDKL5. The channels were able to open, but took much longer to close, resulting in larger and more prolonged currents flowing through them. This implies that CDKL5 is necessary to limit calcium entry into cells.

The researchers also used nerve cells derived from stem cells taken from people with CDD, again observing that Cav2.3 phosphorylation was reduced. This suggests that Cav2.3 function is potentially impaired in humans as well as mice.

Mutations in Cav2.3 that enhance channel activity are already known to cause severe early-onset epilepsy in a related disease called DEE69, which shares many of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders and that inhibition of Cav2.3 could help relieve symptoms such as seizures.

Sila Ultanir, Senior Group Leader of the Kinase and Brain Development Laboratory at Crick, said: “At present, there is a clear need for drugs that specifically target the biological nature of CDD. We established a molecular link between CDKL5 and Cav2. .3, mutations that produce similar disorders. Inhibition of Cav2.3 could be an avenue for testing future targeted treatments.

Marisol Sampedro-Castañeda, postdoctoral researcher at Crick and first author, said: “Our research highlights for the first time a CDKL5 target with a link to neuronal excitability. There is scattered evidence that this calcium channel may be involved in other types of epilepsy. we therefore believe that Cav2.3 inhibitors could potentially be tested more widely.

“Our findings have implications for a large group of people, from families affected by these diseases to researchers working in the rare field of epilepsy.”

Jill Richardson, Executive Director and Head of Neuroscience Biology at MSD, said: “MSD is proud of this innovative research resulting from collaboration with researchers at the Crick and UCL. We have collectively deepened our scientific understanding of biological targets associated with etiologies. of developmental epileptic encephalopathies – an understanding that we hope will contribute to scientific progress in this important area of ​​high and unmet medical need.

The researchers are currently working with Lario Therapeutics, a recently launched biotechnology company seeking to develop first-in-class CaV2.3 inhibitors as precision medicines to treat CDD and related neurodevelopmental syndromes.