New treatment target found for CDKL5 deficiency disorder

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Francis Crick Institute scientists have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy.

CDD causes seizures and impaired development in children, and medications are limited to managing the symptoms rather than addressing the root cause of the disease. The disorder involves the 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 therapy target for CDD, the team has now identified a potential new way to treat CDD by increasing the activity of another enzyme to compensate for the loss of CDKL5.

The study was published today molecular psychiatry, The scientists studied mice that did not produce the CDKL5 enzyme. These mice show symptoms similar to people with CDD, such as impaired learning or social interaction.

The researchers first identified that CDKL5 was active in nerve cells in mice 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 made.

Importantly, even in mice that did not produce CDKL5, some EB2 phosphorylation still occurred, suggesting that another similar enzyme might also be able to phosphorylate it.

By looking at enzymes like CDKL5, the researchers identified one called CDKL2 that targets EB2 and is present in human neurons. In mice lacking both CDKL5 and CDKL2, residual EB2 phosphorylation is almost completely abolished.

The researchers concluded that, although most of the activity comes from CDKL5, about 15% comes from CDKL2, and the remaining <5% from other enzymes yet to be identified.

Their research suggests that increasing CDKL2 levels in people with CDKL5 deficiency could potentially treat some of the effects on the brain in early development.

CDD is a devastating condition that affects young children from birth, and we don’t know why the loss of this one enzyme is so devastating to the developing brain. Through this study, we have identified a potential way to compensate for the loss of CDKL5. “If we can increase the level of CDKL2, we may one day be able to stop symptoms from developing or worsening.”

Cila Ultanir, group leader in the Kinases and Brain Development Laboratory at The Francis Crick Institute

The researchers are now investigating whether mice without CDKL5 can be treated by stimulating their brain cells to make more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new drugs for CDD.

Margaux Silvestre, Crick’s former PhD student and now a postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: “Our findings provide new insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2, a potential compensatory enzyme, offers hope for better treatments. Doing so can make a real difference to the lives of children with this devastating condition. This research owes much to the success of all the authors involved in the publication, as well as the unwavering support we received from technical. The teams at CREEK – a big shout out to them!”

The research was funded by the Lolu Foundation, a non-governmental foundation dedicated to developing therapeutics and eventual cures for CDD.


Journal Reference:

Silvestre, M., etc (2024). Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry.

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