There are rare epilepsies that manifest in early childhood, as occurs with epileptic and developmental encephalopathies. One of the most common types of genetic epilepsy is CDKL5 deficiency disorder (CDD), a disease that is due to alterations in the CDKL5 (cyclin-dependent kinase-like 5) gene, which is responsible for giving instructions for generating a key protein for the development of the brain and its neurons. The mutation in this gene causes an error in the production of the protein and alters the functioning of the brain, as explained by the Association of CDKL5 Affected Persons.
This childhood epilepsy causes seizures and developmental disorders in patients and the treatments available so far are based on generic antiepileptic drugs because no specific medications have been developed. Now, a group of researchers from the Francis Crick Institute, UCL and MSD have identified a possible therapeutic target for this genetic type of epilepsy.
The mechanisms by which genetic mutations in CDKL5 cause CDD are not known. The authors of the new study examined mice lacking the CDKL5 gene and used a technique called phosphoproteomics to look for proteins that are a target of the CDKL5 enzyme. Their findings have been published in Nature Communications.
In this way, they identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, stimulating the cell and allowing it to transmit electrical signals. This is necessary for the nervous system to function properly, but too much calcium in the cells can lead to overexcitability and seizures.
Next, the researchers recorded the calcium channels to see what happened when CDKL5 did not phosphorylate them. The channels were able to open, but took much longer to close, causing larger and longer currents to flow through them. This demonstrates that CDKL5 is necessary to limit calcium entry into cells.
A therapy against CDKL5 deficiency syndrome
The researchers also used nerve cells derived from stem cells taken from people with CDD and again observed that Cav2.3 phosphorylation was reduced. This suggests that the function of Cav2.3 is potentially altered in both humans and mice. Mutations in Cav2.3 that enhance the channel’s activity are already known to cause severe early-onset epilepsy in a related condition called DEE69, which shares many of the same symptoms of CDD. These results suggest that overactivity of Cav2.3 is a common feature of both disorders and that inhibition of Cav2.3 could help with symptoms such as seizures.
“Right now, there is a clear need for medications that specifically target the biological nature of CDD. We have established a molecular link between CDKL5 and Cav2. .3, mutations that produce similar disorders. “Inhibition of Cav2.3 could be a route for trials of future targeted treatments,” said Sila Ultanir, senior group leader at the Crick’s Brain Development and Kinases Laboratory.
Marisol Sampedro-Castañeda, a postdoctoral researcher at the 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 could be involved in other types of epilepsy as well, so we believe that Cav2.3 inhibitors could eventually 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 field of rare epilepsy.”
“Our findings have implications for a large group of people, from families affected by these diseases to researchers working in the field of rare epilepsy”
Jill Richardson, CEO and head of neuroscience biology at MSD, said: “MSD is proud of this groundbreaking research resulting from a collaboration with researchers at the Crick and UCL. Collectively, we have expanded our scientific understanding of the biological targets associated with etiologies. of developmental epileptic encephalopathies: an understanding that we hope will contribute to scientific progress in this important area of great unmet medical need.”
The team of researchers is currently working with the newly formed biotechnology company Lario Therapeutics with the goal of developing first-in-class CaV2.3 inhibitors as precision medicines to treat CDD and neurodevelopmental syndromes. related.
