Reporting in Molecular Psychiatry, scientists at the Francis Crick Institute in London have unveiled a potential breakthrough in the treatment of CDKL5 deficiency disorder (CDD), a prevalent form of genetic epilepsy that affects children worldwide.
CDD is characterized by debilitating seizures and developmental delays, with current treatment options limited to symptom management rather than addressing the underlying cause of the disease.
The research, led by Sila Ultanir, group leader of the Kinases and Brain Development Laboratory at the Francis Crick Institute, focuses on restoring the function of the CDKL5 enzyme, which plays a crucial role in attaching phosphate molecules to proteins, thereby altering their function. Previous studies from the same lab had identified a calcium channel as a potential therapy target for CDD. Building on this foundation, the team has now identified a new approach to potentially treat CDD by augmenting the activity of another enzyme to compensate for the loss of CDKL5.
Using mouse models lacking the CDKL5 enzyme, the researchers observed significant similarities between these mice and individuals with CDD, including impaired learning and social interaction. Surprisingly, despite the absence of CDKL5, there was still evidence of phosphorylation of EB2, a key protein targeted by CDKL5, suggesting the existence of alternative pathways for protein phosphorylation.
Further analysis revealed that a closely related enzyme, CDKL2, also targets EB2 and is present in human neurons. Importantly, in mice lacking both CDKL5 and CDKL2, phosphorylation of EB2 nearly stopped altogether. This discovery led the researchers to conclude that while CDKL5 accounts for the majority of EB2 phosphorylation, approximately 15 percent is attributed to CDKL2, with the remaining fraction likely involving an unidentified enzyme.
“These findings offer a glimmer of hope for individuals affected by CDD,” remarked Ultanir. “By enhancing the levels of CDKL2, we may potentially mitigate the adverse effects on the developing brain, ultimately alleviating symptoms and improving quality of life.”
According to the scientists, the next phase of the research involves investigating whether stimulating brain cells to produce more CDKL2 can effectively treat mice lacking CDKL5. Additionally, the team is collaborating with biotechnology companies to identify molecules capable of increasing CDKL2 levels, paving the way for novel therapeutic interventions for CDD.
Margaux Silvestre, former PhD student at the Francis Crick Institute and now a postdoctoral researcher at the Max Planck Institute for Brain Research, emphasized the significance of the findings, stating, “Our discoveries not only shed light on the expression and regulation of CDKL5 in the brain but also hold promise for the development of improved treatments that could make a meaningful difference in the lives of children battling this devastating condition.”
As the scientific community awaits further developments, this research offers optimism for individuals and families affected by CDD, underscoring the important contributions of collaborative research efforts in uncovering the mysteries of genetic epilepsy and advancing targeted therapies.