Newswise — Researchers at the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy.
Developmental and epileptic encephalopathies are rare types of epilepsy which start in early childhood. One of the most common types of genetic epilepsy, CDKL5 deficiency disorder (CDD), causes seizures and impaired development. Children are currently treated with generic antiepileptic drugs, as there aren’t yet any disease-targeting medications for this disorder.
CDD involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function. Until now, researchers have not been sure how genetic mutations in CDKL5 cause CDD.
Through their research, published today in Nature Communications, the researchers examined mice which lacked the Cdkl5 gene, and used a technique called phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme.
They identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. This is needed for the nervous system to function properly, but too much calcium coming into cells can result in overexcitability and seizures.
The researchers then recorded from the calcium channels to see what was happening when they were not being phosphorylated by CDKL5. The channels were able to open, but were taking a lot longer to close, leading to larger and more prolonged currents flowing through them. This implies that CDKL5 is needed to limit calcium entry into cells.
The researchers also used nerve cells derived from stem cells taken from people with CDD, again observing that phosphorylation of Cav2.3 was reduced. This suggests that Cav2.3 function is potentially altered in humans as well as mice.
Mutations in Cav2.3 that enhance channel activity are already known to cause severe early onset epilepsy in a related condition called DEE69, which shares a lot of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures.
Sila Ultanir, Senior Group Leader of the Kinases and Brain Development Laboratory at the Crick, said: “At the moment, there’s a clear need for drugs which specifically target the biological nature of CDD. 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.”
Marisol Sampedro-Castañeda, postdoctoral researcher at the Crick, and first author, said: “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.”
This research was funded by MSD and the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.
Jill Richardson, Executive Director and Head of Neuroscience Biology at MSD, said: “MSD is proud of this innovative research resulting from a collaboration with researchers at the Crick and UCL. We have collectively furthered our scientific understanding of the biological targets associated with the aetiologies of Developmental Epileptic Encephalopathies – an understanding we hope will contribute toward scientific progress in this important area of high, unmet medical need.”
The researchers are now working with Lario Therapeutics, a recently launched biotech company which is seeking to develop first-in-class CaV2.3 inhibitors as precision medicines to treat CDD and related neurodevelopmental syndromes.
-ENDS-
For further information, contact: [email protected] or +44 (0)20 3796 5252
Notes to Editors
Reference: Sampedro-Castañeda, M. et al. (2023). Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. Nature Communications. 10.1038/s41467-023-43475-w.
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.
An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.
The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.
About MSD
At MSD, known as Merck & Co., Inc., Rahway, NJ, USA in the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.msd-uk.com and connect with us @MSDintheUK on Twitter, LinkedIn, Instagram, YouTube and Facebook.
About UCL – London’s Global University
UCL is a diverse global community of world-class academics, students, industry links, external partners, and alumni. Our powerful collective of individuals and institutions work together to explore new possibilities.
Since 1826, we have championed independent thought by attracting and nurturing the world's best minds. Our community of more than 50,000 students from 150 countries and over 16,000 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems.
The Times and Sunday Times University of the Year 2024, we are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact.
We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors.
For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge.
We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today. We are UCL.
www.ucl.ac.uk | Follow @uclnews on Twitter | Read news at www.ucl.ac.uk/news/ | Listen to UCL podcasts on SoundCloud | View images on Flickr | Find out what’s on at UCL Minds.
RSS