Innovative Models for In Vitro Detection of Seizure
ApconiX is delighted that Dr Kim Rockley’s article ‘ Innovative models for in vitro detection of seizure‘ has now been accepted for publication in Toxicology Research.
The article highlights how new technologies such as microelectrode array and ion channel screening offer the opportunity to screen for seizure liability in vitro, avoiding costly failures in preclinical and clinical development.
Seizures are characterised by uncontrolled activity in the brain which can pose a significant safety concern in drug development. The occurrence of drug attrition in clinical development due to CNS organ toxicity (including seizure) illustrates the limited predictability of current nonclinical seizure-detection models, and points towards a need for improved human-based nonclinical models to accurately predict seizure liability earlier. This review article evaluates the potential of human derived induced pluripotent stem cell neuronal cultures to improve safety screening with an ion channel focussed approach. The link between ion channels and seizure is well known, therefore evaluation of the seizurogenic potential and ion channel profiling of these cells could provide a mechanistic approach to nonclinical seizure detection. The merits of an ion channel in vitro screening approach are discussed, which could culminate in an ion channel-based seizure panel screen to identify and eliminate new drugs that carry CNS risk earlier, before resources, animals and time have been wasted.
Abstract:
Data show that toxicity to the central nervous system (CNS) is the most frequent cause of safety failures during the clinical phase of drug development. CNS endpoints such as seizure pose a safety risk to patients and volunteers and can lead to a loss of competitiveness, delays, and increased costs. Current methods rely on detection in the nonclinical rodent and non-rodent studies required to support clinical trials. There are two main issues with this approach; seizure may be missed in the animal studies and, even if seizure is detected, significant resource has already been invested in the project by this stage. Thus, there is a need to develop improved screening methods that can be used earlier in drug discovery to predict seizure. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. Human derived induced pluripotent stem cells (hiPSCs) representative of almost all cellular subtypes present in the brain can be incorporated into physiologically relevant in vitro models that can be used to determine seizure risk using high-throughput methods. Akin to the success of screening against a panel of ion channels such as hERG to reduce cardiovascular safety liability, the involvement of ion channels in seizure suggests that a similar approach to early seizure detection is valid. Profiling of the ion channels expressed in hiPSC models showing the seizurogenic phenotype coupled with electrophysiological assessment of ion channel function could translate into an ion channel seizure panel for rapid and reliable in vitro detection of seizure. The mechanistic information gathered would support optimal drug design early in development before resources, animals and time have been wasted.
