Research team
Network-based computational drug repurposing for the treatment of KCNQ2-encephalopathy.
Abstract
Developmental and epileptic encephalopathy (DEE) caused by pathogenic variants in the KCNQ2 gene is a severe, early-onset neurological disorder characterised by neonatal seizures and developmental delay. Although seizures can be controlled in many KCNQ2-DEE patients with anti-seizure medication, there are no treatments that address the developmental problems. As a result, these children require intensive care for the rest of their lives. Given the slow and expensive nature of the drug discovery process, the prospects of providing safe and effective treatments for KCNQ2-DEE patients in a short term remain low. In this project, I will combine state-of-the-art in vitro brain organoids with transcriptomic technology, innovative electrophysiological readout systems and a computational prediction strategy to develop a drug screening platform to repurpose well-characterised FDA-approved drugs. This approach will provide unprecedented insight into the underlying molecular pathology of KCNQ2-DEE together with the potential to identify novel drug candidates for this disorder. If successful, the drug screening platform can be extended to other neurodevelopmental disorders for drug compound identification.Researcher(s)
- Promoter: Weckhuysen Sarah
- Co-promoter: Ellender Tommas
- Fellow: Zonnekein Noortje
Research team(s)
Project type(s)
- Research Project
Unraveling the role and contribution of neurons and microglia to the neurodevelopmental problems seen in children with KCNQ3 gain-of-function encephalopathy.
Abstract
Kv7.2 and Kv7.3 subunits, encoded by KCNQ2 and KCNQ3, form homo- or hetero-tetrameric voltage-gated potassium channels (Kv7 channel). Kv7 channels expressed in neurons produce a well characterized M-current that is a critical regulator of neuronal excitability by dampening repetitive firing. Gain-of-function (GoF) variants in KCNQ2 and KCNQ3 lead to severe early-onset neurodevelopmental disorders (KCNQ2- and KCNQ3-GoF-Encephalopathy). However, autism spectrum disorder (ASD) is a much more prominent feature in KCNQ3-GoF-Encephalopathy. This suggests for a Kv7.3 unique function during neurodevelopment. Interestingly, single nuclei RNA sequencing databases have revealed that KCNQ3 is the only KCNQ gene that is highly expressed in microglia in the human brain. Given the emerging evidence that microglia dysfunction is involved in the development of NDD and ASD, we hypothesize that KCNQ3-GoF variants affect microglia function which contributes to the already dysfunctional neuronal network. In this project, I will build a human tripartite neuronal-microglia model (excitatory neurons, inhibitory neurons and microglia) derived from induced pluripotent stem cells that carry KCNQ-GoF variants, as well as control lines. With this model I will (i) investigate the function of Kv7.3 in microglia and (ii) unravel the contribution of each cell type to KCNQ3-GoF-Encephalopthy. Furthermore, this model will be used as a screening platform to perform a proof-of-concept study for RNA interference using antisense oligonucleotides as a targeted treatment strategy for KCNQ3-GoF-Encephalopathy. When successful, this approach could be extended to other types of neurodevelopmental disorders and drug screenings.Researcher(s)
- Promoter: Weckhuysen Sarah
- Co-promoter: Ellender Tommas
- Fellow: Zonnekein Noortje
Research team(s)
Project type(s)
- Research Project