Researchers identify potential way to treat genetic epilepsy by replacing ‘lost’ enzyme

Scientists at the Francis Crick Institute have discovered a new therapeutic target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy.

CDD causes seizures and developmental disabilities in children, and medications are limited to managing symptoms rather than addressing the root cause of the condition. The disorder involves loss of function of a gene producing the enzyme CDKL5, which phosphorylates proteins, meaning it adds an extra phosphate molecule to change their function.

Following recent research from the same lab showing that a calcium channel could be a target for treating CDD, the team has now identified a new way to potentially treat CDD by stimulating the activity of another enzyme to compensate. loss of CDKL5.

In research published in Molecular Psychiatry, scientists studied mice that did not make the CDKL5 enzyme. These mice show symptoms similar to those of people with CDD, such as problems learning or social interactions.

The researchers first identified that CDKL5 is active in mouse nerve cells, but not in another type of brain cell called astrocytes. In nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 is not produced.

Interestingly, even in mice that did not produce CDKL5, some phosphorylation of EB2 occurred, which suggested that another similar enzyme must also be capable of phosphorylating it.

By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice lacking CDKL5 and CDKL2, the remaining EB2 phosphorylation was almost completely disappeared.

The researchers concluded that although most of the activity comes from CDKL5, approximately 15% comes from CDKL2 and the remaining <5% comes from another yet-to-be-identified enzyme.

Their research suggests that increasing the level of CDKL2 in people deficient in CDKL5 could potentially address some of the effects on the brain during early development.

Sila Ultanir, group leader of the Kinase and Brain Development Laboratory at Crick, said: “CDD is a devastating disease that affects young children from birth, and we don’t know much about why the loss of this enzyme is so disastrous for them. “

Researchers are currently studying whether mice lacking CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new CDD drugs.

Margaux Silvestre, former doctoral student. student at Crick and now a postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: “Our findings offer new insights into the expression and regulation of CDKL5 in the brain. Additionally, the identification of CDKL2 as a potential compensatory enzyme provides hope for discovering better treatments that could truly make a difference in the lives of children with this devastating disease. This research owes its success to all the authors involved in the publication but also to the unwavering support we received from the technical teams at the Crick—congratulations to them.”