Discovering "Molecular Hallmarks" And "Master Regulators" In Epilepsy

By Christian Wolff, head of epilepsy discovery research, UCB

Epilepsy, with its diverse clinical presentations and complex underlying biologies, presents difficulties when searching for potential new treatments. While important advances have been made in understanding the complexity of this disease, considerable challenges remain. We not only need to correctly match the right biology to each patient population, but we also need to understand the optimal timing of intervention post-diagnosis, especially for new therapies with disease-modifying properties. The critical opportunity window is where people living with epilepsy have the best chance of potentially gaining control over their seizures.

Over the next few years, I predict that epilepsy research will look to address challenges across three core areas of interest to UCB:

1. Furthering our understanding of the root causes of epilepsies, including focusing on the non-seizure outcomes (in addition to seizures)
2. Further establishing new treatment pathways for more targeted therapies, including potential disease modification approaches
3. Filling the translational gaps from research to the clinic

As we look into the future, understanding the molecular hallmarks of epilepsies will be vital, and insights into the genetics and disease pathways will play a key role in transforming our understanding of epilepsies. This will enable personalized treatment approaches for those living with epilepsy and uncover novel therapeutic targets.

Next-generation therapies that have disease-modifying potential offer a promising option, moving beyond seizure management to address the broader spectrum of symptoms experienced by those living with epilepsy.

There is a lot of talk within the industry about the importance of understanding the molecular hallmarks of epilepsies. What is a “molecular hallmark” and how does it differ from a “master regulator” in understanding complex epilepsies?

In epilepsy research, molecular hallmarks and master regulators are two key concepts that help us better understand the underlying mechanisms and root causes of epilepsies.

Molecular hallmarks are unique molecular signatures linked to the disease biology of different types of epilepsies. They include, for example, changes in gene expression, protein levels, and cell signaling. These molecular hallmarks may be considered as fingerprints, providing insights into distinct and overlapping biologies across disease etiologies and thus helping to characterize epilepsy subtypes and offering new insights into therapeutic target mechanisms.

In contrast, a master regulator represents a central node or regulatory molecule, upstream of the dysregulated gene networks, and is predicted to modulate multiple disease pathways, making it a potential target for restoring normal gene activity. Unlike molecular hallmarks, which are the biological fingerprints of epilepsies, a master regulator represents a potential point of intervention to control or restore dysfunctional gene network activity and hence offers the opportunity to develop novel disease-modifying therapies in epilepsy.

UCB and collaborators have made significant progress toward identifying a single master regulator that may work across different structural epilepsies. What was the initial goal discussed at UCB when starting work to identify a single master regulator?

The initial goal for applying a system network analysis was to establish a deeper understanding of the disease biology in epilepsy. We are collaborating with key experts in the field to build a strong analytical framework that we initially applied to rodent models and where we identified CSF1R as a potential master regulator in drug-resistant epilepsy. We have now expanded our knowledge to human disease biology, with the ambition of identifying molecular targets that could impact the disease biology. The pursuit of identifying a master regulator that could show potential for treatment across different structural epilepsies remains a key pillar of our epilepsy research strategy at UCB. This feeds into our aspiration to move beyond symptomatic treatments of epilepsies to disease-modifying solutions that target the underlying pathobiology. We have made significant progress in this research, but further evaluation is necessary.

How does identifying a master regulator benefit our understanding of epilepsy pathobiology and the development of potential treatments?

It’s about enabling our understanding of the underlying disease biology in the epilepsies and identifying druggable targets for new therapies. Identifying master regulators offers an opportunity to explore the specificities and commonalities of dysregulated gene networks across epilepsy subtypes. Furthermore, master regulators may be used as tools to further validate that dysregulated gene networks, identified in human disease, are also present and are key drivers of the pathology in preclinical animal models. These are important considerations for exploring the impact of new therapies early in the drug development process and ensuring that findings can be efficiently translated to the clinic. We have recently applied this approach to structural epilepsies and we are now expanding this work to genetic epilepsies with the goal of identifying targets with disease-modifying potential and that could be applied across multiple genetic disorders.

How has the progress UCB has made supported both the research and UCB’s long-term pipeline?

From a research perspective, one recent example is the collaboration with GliaPharm, which was established based on the exploration of master regulators in human epilepsy. This work supports our internal research in astrocyte biology, which explores the function of glial cells under disease conditions in the brain. This research has established in vitro disease models to potentially enable the validation of novel therapeutic targets.

In terms of our pipeline, we're working to uncover new biological insights with the goal of turning them into disease-modifying treatments for specific epilepsy patient populations.

The presentation of complex epilepsies and the offering of targetable mechanisms beyond the traditional channelopathies is a focus at UCB. How have molecular hallmarks helped UCB with this?

In advancing innovative treatment strategies, there must be emphasis on addressing complex forms of epilepsies and identifying targetable mechanisms beyond traditional channelopathies. Molecular hallmarks have played a pivotal role in guiding UCB's research efforts by providing crucial insights into critical disease biologies and the development of novel targeted treatments with disease-modifying properties.

By leveraging molecular hallmarks, UCB has gained a deeper understanding of the molecular subtypes of epilepsy that is leading to the identification of novel therapeutic targets. It also has spurred the exploration of new chronic symptomatic therapies that extend beyond traditional channelopathies and neuronal excitability, focusing instead on elements like energy metabolism, brain network plasticity, and inflammation.

How is AI helping to speed up progress here? Can you give any tangible examples of how this is being used in UCB’s clinical development programs?

The integration of AI into UCB's research and clinical development programs is a key part of our strategy as it can help accelerate progress in epilepsy research and drug discovery. We are currently using AI to support our work around the identification of master regulators and for the development of our disease models.

AI is also becoming increasingly important in epilepsy, as it enables us to look beyond seizures to analyze additional signs and symptoms that are particularly subtle and require technology to identify and monitor. For example, in early phases of our drug discovery efforts, we are now leveraging AI to help identify cellular disease phenotypes emerging from patient-derived iPSC neurons and to analyze complex animal behaviors and electrophysiology signals in genetic models of epilepsy.

I predict AI technologies will be applied to biomarker discovery, which will aid clinical development and monitoring. This will again help expedite the discovery and development of novel therapies for those living with epilepsies and their caregivers.

We know that challenges will persist within epilepsy research, and we constantly need to push our approaches to secure the best outcome for those we serve. Molecular hallmarks and master regulators provide invaluable insights and open new avenues for precision medicine and new treatments that address the unmet needs of people living with epilepsies.

About The Author:

Christian Wolff is the head of epilepsy discovery research at UCB. Wolff obtained his Ph.D. in biochemistry and has contributed to epilepsy research and drug discovery at UCB for more than 20 years.