A notable study conducted by the Francis Crick Institute, UCL, and MSD has made a significant discovery in the field of epilepsy research, particularly in addressing CDKL5 deficiency disorder, a form of genetic epilepsy. The study has pinpointed the Cav2.3 calcium channel as a crucial element in this disorder, paving the way for new treatment methods using Cav2.3 inhibitors.
The collaborative research effort has highlighted a promising new target for treating this genetic epilepsy. CDKL5 deficiency disorder, a prevalent form of genetic epilepsy that emerges in early childhood, leads to seizures and developmental challenges. Presently, children with this condition are treated using general antiepileptic drugs, as there are no specific treatments targeting this disorder.
The disorder is characterized by the loss of function of a gene responsible for producing the CDKL5 enzyme. This enzyme plays a role in protein phosphorylation, which involves the addition of a phosphate molecule to change protein functions. The exact mechanism by which CDKL5 genetic mutations lead to the disorder was previously unclear.
In the latest study, published on December 11 in Nature Communications, the researchers employed phosphoproteomics in mice lacking the Cdkl5 gene to identify proteins that the CDKL5 enzyme targets.
Exploring the Role of Calcium Channels
Cav2.3, a calcium channel, was identified as a significant target. This channel facilitates the entry of calcium into nerve cells, essential for nerve cell excitation and transmission of electrical signals. However, excessive calcium entry can lead to cell overexcitability and seizures.
Investigations into these calcium channels revealed altered closing times when not phosphorylated by CDKL5, resulting in prolonged and amplified currents. This finding suggests that CDKL5 is crucial for regulating calcium entry into cells.
Further studies using nerve cells derived from stem cells of individuals with CDD showed similar findings, indicating that Cav2.3’s role might extend to humans as well as mice.
Connecting Cav2.3 to Severe Epilepsy
It is known that mutations in Cav2.3 that increase channel activity lead to severe early-onset epilepsy in a related condition, DEE69, which shares symptoms with CDD. These findings imply that overactivity of Cav2.3 is a common aspect of both conditions, suggesting that Cav2.3 inhibitors could be beneficial in treating symptoms such as seizures.
Sila Ultanir, from the Kinases and Brain Development Laboratory at the Crick, emphasizes the need for drugs targeting the biological nature of CDD. The link between CDKL5 and Cav2.3 mutations, which result in similar disorders, opens the possibility of Cav2.3 inhibitors being tested in future targeted treatments.
Marisol Sampedro-Castañeda, a postdoctoral researcher at the Crick and the study’s first author, highlights the significance of identifying a CDKL5 target linked to neuronal excitability. The potential involvement of this calcium channel in other epilepsy types suggests that Cav2.3 inhibitors might have broader applications.
This research, funded by MSD and the Loulou Foundation, holds implications for a wide audience, from affected families to researchers in the field of rare epilepsy.
Next Steps
Jill Richardson of MSD commends the collaborative research that has advanced the understanding of biological targets in Developmental Epileptic Encephalopathies. This progress is hoped to contribute significantly to scientific advancements in this area of critical medical need.
The researchers are currently collaborating with Lario Therapeutics to develop first-in-class CaV2.3 inhibitors as precision medicines for treating CDD and related neurodevelopmental syndromes.
Reference: “Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability,” published on December 11, 2023, in Nature Communications.
DOI: 10.1038/s41467-023-43475-w
Table of Contents
Frequently Asked Questions (FAQs) about CDKL5 Genetic Epilepsy Treatment
What is the key discovery in the study on CDKL5 deficiency disorder?
The study by the Francis Crick Institute, UCL, and MSD discovered that the Cav2.3 calcium channel is a key factor in CDKL5 deficiency disorder, a form of genetic epilepsy. This discovery opens up the potential for new treatments using Cav2.3 inhibitors.
How does the CDKL5 enzyme affect epilepsy?
The CDKL5 enzyme is involved in phosphorylating proteins, a process that alters their function. The study found that mutations in CDKL5 affect the function of the Cav2.3 calcium channel, leading to increased cell excitability and seizures.
What are the implications of identifying Cav2.3 as a target in epilepsy treatment?
Identifying Cav2.3 as a target suggests that inhibiting this calcium channel could help manage symptoms like seizures in genetic epilepsy, specifically CDKL5 deficiency disorder. It represents a new potential treatment path.
How does the study contribute to the understanding of genetic epilepsy?
The study provides insights into the molecular mechanisms of CDKL5 deficiency disorder and establishes a link between CDKL5 mutations and alterations in calcium channel function, advancing the understanding of the biological basis of genetic epilepsy.
What are the future steps following this research?
The researchers are now collaborating with Lario Therapeutics to develop CaV2.3 inhibitors as precision medicines. These are aimed at treating CDKL5 deficiency disorder and related neurodevelopmental syndromes, marking a significant step towards targeted therapies.
More about CDKL5 Genetic Epilepsy Treatment
- Francis Crick Institute Research on Genetic Epilepsy
- Nature Communications Journal Article
- CDKL5 Deficiency Disorder Information
- Cav2.3 Calcium Channel and Epilepsy
- MSD Research Initiatives
- Lario Therapeutics and Neurodevelopmental Treatment
4 comments
its about time we had more focused treatments for these rare conditions, i know a family affected by cdkl5 deficiency, this could be a game changer for them. Kudos to the researchers!
Gotta say, science is amazing. The fact they can now link specific genes and channels like CDKL5 and Cav2.3 to disorders and possibly treat them? Mind blowing stuff.
wow, this is incredible news! such advancements in epilepsy treatment could really change lives especially for those affected by genetic forms like CDKL5. Really hope this leads to new effective treatments.
interesting read, but how long until these treatments are actually available? feels like theres always a big gap between discovery and real world applications. Lets hope it’s different this time.