Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability
We previously published about this research in a story titled “Researchers Identify Potential CDKL5 Treatment Target” which can be found here. The study was originally published in the scientific journal Nature Communications. You can read the full text of the study here.
What Happened?
CDKL5 deficiency disorder (CDD) is an uncommon genetic disorder that leads to developmental delays and epilepsy. Generally, treatment of this order involves the use of standard antiepileptic medications, and while these can be effective at times, no targeted therapies specifically for CDKL5 have been developed.
The CDKL5 gene plays an important function by adding an extra phosphate protein to molecules, which changes their function. This process is called phosphorylation. Until recently, scientists weren’t sure how mutations of this gene triggered the development of this disorder. This study sought to find and answer to this question, and in the process, find a potential therapeutic target for CDKL5 deficiency disorder.
The researchers utilized a mouse model of the deficiency disorder with mice that lacked the CDKL5 gene entirely. The team used a technique called phosphoproteomics in order to search for the proteins that the CDKL5 enzyme acts upon. They were able to identify a calcium channel protein called Cav2.3, which allows for calcium to enter nerve cells. While this is critical for normal function of the nervous system, excessive calcium entering the cell can lead to overexcitability and seizure events.
Without CDKL5, the channels were still able to open, but they stayed open for much longer. Therefore, CDKL5 plays a moderating role in how long the channels are open, therefore keeping calcium levels in the cells in check. The team also looked at neurons derived from stem cells taken from CDKL5 patients. The same effect was seen in these cells as was seen in the mouse model cells.
The researchers concluded that Cav2.3 could be a viable target in this disorder. A therapy that could inhibit the activity of the protein could help reduce symptoms.
Why Does it Matter?
The findings from this research could be the first step in developing a disease-altering therapy for CDKL5 deficiency disorder. However, the results could have even broader implications:
“Our research highlights for the first time a CDKL5 target with a link to neuronal excitability. There’s scattered evidence that this calcium channel could be involved in other types of epilepsy too, so we believe that Cav2.3 inhibitors could eventually be tested more widely. Our findings have implications for a large group of people, from the families affected by these conditions to researchers working in the rare epilepsy field.” – Marisol Sampedro-Castañeda, first author, postdoctoral researcher, Francis Crick Institute
The team is in talks with Lario Therapeutics, a biotech company that is planning to develop Cav2.3 inhibitors.
“We’ve made a molecular link between CDKL5 and Cav2.3, mutations in which produce similar disorders. Inhibiting Cav2.3 could be a route for trials of future targeted treatments.” – Sila Ultanir, Senior Group Leader, Kinases and Brain Development Laboratory, Francis Crick Institute
About CDKL5 Deficiency Disorder
CDKL5 deficiency disorder is a genetic disorder which is characterized by intellectual disability, seizures, and developmental delays. As the name suggests, the disorder is linked to mutations of the CDKL5 gene which usually occurs spontaneously and is not inherited from a person’s parents. Symptoms become noticeable in the first few months of life. Females are affected more frequently than males, but males tend to have more severe symptoms. These symptoms can include seizures (1-5 per day), constipation, distinctive facial features, reflux, teeth grinding, and problems with feeding and sleeping. Treatment options for CDKL5 deficiency disorder are limited and are primarily focused on minimizing symptoms. Some patients may require a feeding tube. There is a serious need for new and more effective therapies to treat this disorder. In order to learn more about CDKL5 deficiency disorder, click here.
