July 16, 2024

New potential treatment target identified for genetic type of childhood epilepsy affliction

Researchers from the Francis Crick Institute, UCL, and MSD have identified a potential treatment target for a genetic type of epilepsy that starts in early childhood. This type of epilepsy, known as CDKL5 deficiency disorder (CDD), is a rare form of developmental and epileptic encephalopathies that causes seizures and impaired development in affected children. Currently, children with CDD are treated with generic antiepileptic drugs, as there are no specific medications available for this disorder.

CDD occurs when there is a loss of function in the gene that produces the CDKL5 enzyme, which is responsible for phosphorylating proteins. Phosphorylation is a process that involves adding an extra phosphate molecule to alter the function of proteins. Up until now, researchers have not fully understood how genetic mutations in CDKL5 lead to the development of CDD.

In their study published in Nature Communications, the researchers conducted experiments on mice that lacked the Cdkl5 gene. They utilized a technique called phosphoproteomics to scan for proteins that are targeted by the CDKL5 enzyme. Through their investigation, they identified a calcium channel called Cav2.3 as a target of the CDKL5 enzyme.

Cav2.3 is responsible for allowing calcium to enter nerve cells, which excites the cell and enables the transmission of electrical signals. While calcium entry is crucial for proper nervous system functioning, an excessive influx of calcium can lead to over-excitability and seizures. The researchers observed that when Cav2.3 was not phosphorylated by CDKL5, the calcium channels took longer to close, resulting in larger and more prolonged electrical currents flowing through them. This suggests that CDKL5 plays a role in limiting calcium entry into nerve cells.

Furthermore, the researchers examined nerve cells derived from stem cells taken from individuals with CDD and found that phosphorylation of Cav2.3 was reduced. This suggests that Cav2.3 function may also be altered in humans, not just in mice.

Interestingly, mutations in Cav2.3 that enhance channel activity have already been linked to severe early onset epilepsy in a related condition called DEE69, which shares many symptoms with CDD. These findings indicate that Cav2.3 over-activity is a common characteristic of both disorders, and inhibiting Cav2.3 could potentially alleviate symptoms such as seizures.

Sila Ultanir, Senior Group Leader of the Kinases and Brain Development Laboratory at the Crick, expressed the need for drugs that specifically target the biological nature of CDD. Inhibiting Cav2.3 could be a potential avenue for future targeted treatments. Marisol Sampedro-Castañeda, a postdoctoral researcher at the Crick and the first author of the study, emphasized the importance of their findings in establishing a CDKL5 target with a connection to neuronal excitability. The team believes that Cav2.3 inhibitors could eventually be tested more widely, as there is scattered evidence suggesting the involvement of this calcium channel in other types of epilepsy as well.

The implications of these findings extend to a broad range of individuals, from affected families to researchers in the rare epilepsy field. Jill Richardson, Executive Director and Head of Neuroscience Biology at MSD, expressed pride in the innovative research resulting from the collaboration between MSD and the Crick and UCL researchers. The improved understanding of the biological targets associated with the cause of Developmental Epileptic Encephalopathies could contribute to significant scientific progress in this essential area of high, unmet medical need.

Moving forward, the researchers will collaborate with Lario Therapeutics, a recently-established biotech company that aims to develop first-in-class CaV2.3 inhibitors as precision medicines for the treatment of CDD and related neurodevelopmental syndromes.

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1. Source: Coherent Market Insights, Public sources, Desk research
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