New target identified for potential novel treatments for rare disorder

Neuroscientists at Trinity College Dublin (TCD), who are studying a rare neurodevelopmental disorder in children, have identified previously unknown target areas for potential new treatments.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare disorder for which there is currently no cure or specific treatment. It is caused by mutations in the CDKL5 gene.

This gene is located on the X chromosome and it provides instructions for making a protein that is essential in forming the connections for normal brain development. Mutations in the gene result in the absence of a functional protein.

CDD affects 1 in 40,000 live births and it primarily affects girls, due to the fact that the gene is located on the X chromosome, one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes and males have one X and one Y.

The condition results in severe epilepsy that develops early in life and does not tend to respond to medication, as well as neurodevelopmental delay that can affect a range of functions, such as motor, cognitive and speech.

There are currently seven known families with a child that has been diagnosed with CDD in Ireland, however researchers warn that the disorder may be underdiagnosed as it currently requires genetic testing.

Researchers are working hard to identify biomarkers and develop new treatments, with the ultimate goal of finding a cure. Research centres around preclinical models, including in vitro and in vivo models.

The use of animal models such as the ‘Cdkl5-knockout mice (KO mice)’, which are mice that lack the Cdkl5 gene, have been an invaluable tool to gather insights into the molecular changes underlying CDD.

The TCD research is focusing on the biology and pharmacology of microtubule dynamics as a biomarker to assess the severity and progress of CDD and as a target to develop novel pharmacological treatments.

Microtubules, which act like large, complex scaffolding structures, play a vital role in the development of brain cells and in supporting the formation, maintenance and remodelling of synapses, which brain cells use to communicate. Dysfunction in microtubule dynamics leads to altered brain development and loss of synapses.

At a recent CDD Family Awareness Day, the TCD researchers announced that alterations in plasma microtubule dynamics observed in animal models of CDD have also been found in plasma samples of CDD patients, confirming the analysis of microtubule dynamics in plasma as a non-invasive biomarker of disease progression in CDD.

This finding will be crucial for families as the progression of the disease can now be monitored in a non-invasive way, which is ultimately better for the patient.

“Finding a translational biomarker (measurable in both animal models and patients) for the severity and progression of CDD is extremely important both for research and for clinical needs.

“Thus, a good biomarker would allow to effectively assess the efficacy of treatments in development by making it possible to directly compare effects in the animal models and in the patients, thus increasing the translational power and significance of the research,” commented Dr Massimiliano Bianchi, adjunct assistant professor at Bianchi’s Lab and founder and president of Ulysses Neuroscience Ltd in the TCD Institute of Neuroscience.

Meanwhile, Dr Bianchi also announced the establishment of the first Irish colony of Cdkl5-KO mice in Ireland, as well as his team’s collaboration with hospitals and CDD family associations worldwide to collect plasma and other biological fluids (saliva or urine) from CDD patients.

Furthermore, there are also plans to implement the first dedicated CDD biobank in the world at TCD. The biobank represents a unique opportunity for researchers around the world to acquire an important number of CDD samples for their research on translational biomarkers of CDD.

Dr Bianchi said that the research team “works as part of a network of dedicated researchers, patients and other stakeholders to improve our understanding of CDD and develop reliable biomarkers that can be used to develop new treatments and monitor clinical disease progression”.

However, he emphasised that the patient “should be at the centre of all medical research”.

“Their needs should be considered holistically, from simple daily needs to complex pharmacological treatments. In line with our ethos, we have a direct line of communication with the families and patients of the disorders we research, and we organise frequent focus groups to assess whether our research goals are in line with the actual concerns of those who live with the disorder,” he added.

For more information on Bianchi’s Lab, click here.