Blog post: The Importance of Fundamental Research in the Treatment of a Rare Form of Epilepsy

By- James Hogg

CDKL5 Deficiency Disorder (CDD) is a rare form of epilepsy identified in approximately 1 in 50,000 births. This is caused by mutations in the CDKL5 gene, which when working correctly produces a protein called CDKL5 (Cyclin Dependent Kinase Like 5) that is vital for proper development of the brain.  

Those affected by CDD often experience a range of symptoms, most notably seizures from ages as early as a few weeks after birth. Despite a short respite from seizures, a few months to years after the initial onset, these can return in abundance.  

Alongside seizures, people commonly experience severe developmental delays, which culminate in poor motor coordination, intellectual disability, and impaired vision amongst other symptoms. These alternative symptoms can persist even if a patient experiences fewer, more controllable seizures. As a result of this, CDD patients usually require constant care, which can put a heavy strain on caregivers.  

There is no specific treatment for CDD, and resistance to anti-seizure medications is common. Recently, approval of the pre-existing anti-seizure medication, Ganaxolone, as a new treatment to control seizures in CDD patients, marked a significant step in the journey to treat this disorder. Furthermore, Fenfluramine, which was originally designed as an appetite suppressant, is in the later stages of clinical trials, with the hope it will also be approved to control seizures in CDD patients. However, these drugs are not usually 100% effective, and can cause a variety of unwanted side effects. They also primarily target seizures as opposed to parallel CDD symptoms, which does not always align with the primary concerns of caregivers.  

Alternatively, exciting new approaches to reintroduce a functional copy of the CDKL5 gene with “gene therapy” have yielded promising results in laboratories. However, these are yet to be tested in human patients. This aims to correct the underlying genetic abnormality rather than just treating the symptoms that arise.  

Having only been categorised as an epileptic disorder in its own right in the early 2000s, the understanding of how mutations in the CDKL5 gene causes seizures and other symptoms remains largely unknown. Therefore, the importance of fundamental research to understand how CDKL5 functions in the brain (and importantly how mutations cause CDD symptoms) cannot be understated. This type of research aims to decipher the mechanism of the disease and is critical to provide new angles for treatment. 

Fundamental research across institutes worldwide in the last 10 - 15 years has begun to unearth the function of CDKL5. This is highlighted by the identification of a range of molecules that CDKL5 both interacts with and modifies. These can be coupled to observations of multiple essential brain processes that no longer work efficiently due to CDKL5 mutations.    

Notably, many of these faulty processes appear to prevent efficient communication between neurons. From this, we can begin investigating different approaches to try and correct these faults, either by using drugs or reintroducing the CDKL5 protein. This can open the possibility of new ways to target the disease or provide information supporting gene therapy strategies.  

Whilst strong progress has been made to understand CDD since its discovery around 20 years ago, there remains a great need to strengthen our knowledge. Therefore, supporting fundamental research of CDD (alongside other rare epileptic disorders) should be a top priority of charities and funding bodies. This will enable further progress into the development of new therapeutics that can have powerful impacts on the lives of those with CDD, and their support networks too.  

Author Bio:  

James is a PhD student at the Centre for Discovery Brain Sciences and Muir Maxwell Epilepsy Centre within The University of Edinburgh. His research is funded by the Epilepsy Research Institute to investigate which brain communication molecules are modified by CDKL5, with aims of identifying the molecular mechanism by which CDKL5 controls this communication. 

References: 

1. Hong, W., Haviland, I., Pestana-Knight, E., Weisenberg, J.L., Demarest, S., Marsh, E.D. and Olson, H.E., 2022. CDKL5 deficiency disorder-related epilepsy: a review of current and emerging treatment. CNS drugs, 36(6), pp.591-604. 

2. Leonard, H., Downs, J., Benke, T.A., Swanson, L., Olson, H. and Demarest, S., 2022. CDKL5 deficiency disorder: clinical features, diagnosis, and management. The Lancet Neurology, 21(6), pp.563-576. 

3. Liu, R., Sun, L., Wang, Y., Wang, Q. and Wu, J., 2023. New use for an old drug: quinidine in KCNT1-related epilepsy therapy. Neurological Sciences, 44(4), pp.1201-1206. 

4. Van Bergen, N.J., Massey, S., Quigley, A., Rollo, B., Harris, A.R., Kapsa, R.M. and Christodoulou, J., 2022. CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development. Biochemical Society Transactions, 50(4), pp.1207-1224. 

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