What are your research topics?
My research aims at a better understanding of the molecular genetic basis of rare epilepsy syndromes with identification of the underlying defective genes as a starting point. This enables establishment of molecular genetic diagnostics for these diseases. In the long term, the research contributes to development of novel therapies for epilepsy.
Our current focus in gene identification is on the rare group of progressive diseases with myoclonus and epilepsy as the major clinical manifestations, the PMEs. We employ genome-wide approaches, i.e. exome and genome sequencing to identify the underlying genes. Our recent work suggests that PMEs have highly heterogeneous genetic etiologies encoding gene involved in a variety of cellular processes. The work is done in international collaboration, the consortium co-headed by me and Prof. Sam Berkovic in Melbourne.
A central focus of research in my team deals with investigation of disease mechanisms underlying the most common PME disease, EPM1, which is caused by partial loss-of-function mutations in the gene encoding cystatin B, a cysteine protease inhibitor. We are utilizing cystatin B -deficient (Cstb-/-) mice and patient-derived induced pluripotent stem cells (iPSC) as models and are applying various omics approaches in our research. We have shown the central contribution of early microglial activation and dysfunction in the disease pathogenesis in Cstb-/-mice, and deciphering the molecular mechanisms associated with microglial dysfunction in EPM1 is an important focus of our research today.
Based on your research, what is (are) the most central, most urgent, or most exciting unresolved question(s) in the epilepsy field?
Molecular genetic studies during the past two decades have unraveled an unprecedented etiological heterogeneity in epilepsy. This concerns both the rare epilepsy syndromes and the common genetic epilepsies with a polygenic and multifactorial etiology. The vast heterogeneity poses challenges for the development and implementation of personalized therapies for genetic epilepsies. Indeed, despite advances in understanding underlying genetic etiologies and disease mechanisms, medical treatment of epilepsy today rarely targets the underlying disease process.
Given the number of identified genes and variants, many with different functional outcomes even within single genes, developing precision therapies for genetic epilepsies is the most urgent, and most challenging task for the epilepsy research community. To achieve this, close collaboration between clinical and translational researchers is essential to identify the most critical needs for targeted therapies. Better functional understanding is needed to enable targeting therapies for functionally similar variants as a group rather than each individual variant separately. Robust preclinical models combined with novel function tools are a prerequisite for success in developing precision therapies for epilepsy. Finally, the epilepsy community needs to prepare for upcoming clinical trials with the precision treatments.
Regarding my own research the most critical question is to understand how partial loss of cystatin B function increases neuronal excitability and impairs neuronal survival during the life of EPM1 patients, resulting in progressive, highly treatment-resistant, and severely disabling myoclonus with cognition being largely preserved. This mechanistic understanding is needed for development of precision therapies for EPM1 patients, primarily for treatment of the disabling myoclonus.