A potential treatment target for a genetic type of epilepsy has been identified, it has been announced.
Researchers at the Francis Crick Institute and at University College London, UK, say they believe their findings could be positive to treat CDKL5 deficiency disorder, one of the most common types of genetic epilepsy.
With CDD a gene producing the CDKL5 enzyme, which phosphorylates proteins, loses its function but it was unknown how genetic mutations in CDKL5 cause CDD.
The new study, published in Nature Communications, examined mice that lacked the Cdkl5 gene, and used phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme.
They identified Cav2.3, a calcium channel, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. It is needed for the nervous system to function properly, but too much calcium entering cells can result in overexcitability and seizures.
The team went on to record from the calcium channels to see what was happening when they were not being phosphorylated by CDKL5. They found the channels opened but took longer to close, which resulted in larger and more prolonged currents flowing through them. This, they say, implies that CDKL5 is needed to limit calcium entry into cells.
The researchers also used nerve cells derived from stem cells taken from people with CDD and observed a reduction in phosphorylation of Cav2.3, suggesting Cav2.3 function is potentially altered in humans as well as mice.
It is already known that mutations in Cav2.3 that enhance channel activity cause severe early onset epilepsy in DEE69, a related condition that shares many CDD symptoms and the researchers say their results suggest Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures, the researchers say.
Sila Ultanir, senior group leader of the Kinases and Brain Development Laboratory at the Crick, said: “At the moment, there’s a clear need for drugs which specifically target the biological nature of CDD.
We’ve made a molecular link between CDKL5 and Cav2.3, mutations in which produce similar disorders. Inhibiting Cav2.3 could be a route for trials of future targeted treatments.”
First author Marisol Sampedro-Castañeda, postdoctoral researcher at the Crick, added: “Our research highlights for the first time a CDKL5 target with a link to neuronal excitability. There’s scattered evidence that this calcium channel could be involved in other types of epilepsy, too, so we believe that Cav2.3 inhibitors could eventually be tested more widely.
“Our findings have implications for a large group of people, from the families affected by these conditions to researchers working in the rare epilepsy field.”
The researchers are now working with Lario Therapeutics, a biotech company that is developing first-in-class CaV2.3 inhibitors as precision medicines to treat CDD and related neurodevelopmental syndromes.
Sampedro-Castañeda M et al. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. Nature Communications 11 December 2023; doi: 10.1038/s41467-023-43475-w.
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