Researchers from the Francis Crick Institute, UCL and MSD have identified a potential therapeutic 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 targeted drugs for this disorder yet.
The results of the study were published on Nature Communications.
Childhood epilepsy: some details on the new research
CDD involves the loss of function of a gene that produces the enzyme CDKL5, which phosphorylates proteins, meaning it adds an extra molecule of phosphate to alter their function. Until now, researchers were unsure how genetic mutations in CDKL5 cause CDD.
Through their research on childhood epilepsy, the researchers looked at mice lacking the Cdkl5 gene and used a technique called phosphoproteomics to look for proteins that are a target for the CDKL5 enzyme.
Scientists have identified a calcium channel, Cav2.3, as a 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 the cells can cause overexcitability and epilepsy.
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, more prolonged currents flowing through them. This implies that CDKL5 is required to limit calcium entry into cells.
The researchers also used nerve cells derived from stem cells taken from people with CDD, again observing that phosphorylation of Cav2.3 was reduced. This suggests that Cav2.3 function is potentially altered in both humans and mice.
Mutations in Cav2.3 that enhance channel activity are already known to cause severe early-onset epilepsy in a related condition called DEE69, which shares many of the same symptoms as CDD. These findings suggest that Cav2.3 hyperactivity is a common feature of both disorders and that inhibiting Cav2.3 could help with symptoms such as epilepsy.
Sila Ultanir, Senior Group Leader of the Kinases and Brain Development Laboratory at the Crick, said: “At the moment, there is a clear need for drugs that specifically target the biological nature of CDD. We have created 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 against childhood epilepsy.”
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.” Furthermore, we believe that Cav2.3 inhibitors could eventually be tested on a larger scale.
“Our findings have implications for a broad group of people, from families affected by these conditions to researchers working in the field of rare epilepsy.”
Jill Richardson, Executive Director and Head of Neuroscience Biology at MSD, said: “MSD is proud of this innovative research resulting from a collaboration with researchers at the Crick and UCL. We have collectively improved our scientific understanding of the biological targets associated with the etiologies of developmental epileptic encephalopathies – an understanding that we hope will contribute to scientific progress in this important area of high unmet medical need.”
The researchers are now working with Lario Therapeutics, a recently launched biotechnology company that is seeking to develop first-in-class CaV2.3 inhibitors as precision medicines for the treatment of CDD and related neurodevelopmental syndromes, such as childhood epilepsy.
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