Seizure Liability

The regulations regarding the testing of new drugs are changing. The FDA modernisation act endorses the use of new approach methodologies (NAMs) to assess of a range of toxicities, including seizure liability which can negatively impact a drug’s probability of success. We have developed an integrated in vitro screening approach for early seizure liability to support hazard identification and decision making in early drug discovery:

  • A panel of 15 human ion channels related to seizure that can be screened using automated electrophysiology
  • A microelectrode array (MEA) assay that utilises human-derived neuronal stem cells to demonstrate potential seizure activity by measuring electrical activity

You will benefit from:

  • High quality ion channel profiling with a turnaround time of 14 days from receipt of compound
  • MEA assessment of electrical activity in human iPSC-neuronal and astrocyte co-cultures
  • High-throughput assays with reduced reliance on costly animal studies with questionable translation
  • Access to ApconiX scientists who will tailor our service specifically to your needs and better advise you on your next steps
ION Channel Screening Services
Apconix 18 scaled 1 | ApconiX

Our Services:

  • Ion channel screening of our comprehensive panel of seizure-associated ion channels performed by automated patch-clamp.  All ion channels are the human isoform: Nav1.1, Nav1.2, Nav1.6, Kv1.1, Kv2.1, Kv3.1, Kv4.2, KCa1.1, KCa4.1, Kv7.2/7.3, Kv7.3/7.5, GABA α1β2γ2, NMDA 1/2A, nicotinic AChR α4β2, Cav2.1
  • Investigation of potential seizurogenicity in hiPSC-neuronal co-cultures using the Maestro Pro MEA assay system (Axion BioSystems)

Investigating Seizure Liability

Inhibition of neuronal ion channels can adversely affect the balance of excitation and inhibition in the brain and negatively impact a drug’s probability of success, value and competitiveness. By working with ApconiX you will benefit from our combined expertise in ion channel electrophysiology, hiPSC-neuronal cell models and project toxicology to identify risks, gain mechanistic insight and prioritise the right candidates moving forward.

Our electrophysiology experts will rapidly generate high-quality seizure panel screening data for your drug discovery programme and aim to return this data in two weeks.

Our hiPSC-neuronal cell model experts can assess compound effects on electrical signalling. This can reveal perturbations to ion channel activity and other important regulators of neuronal function.

MEA video
This video shows synchronicity of action potential firing in
hiPSC-neuronal co-culture.

video | ApconiX

Seizure Liability Posters

sezureposter1 | ApconiX

An integrated approach for early in vitro seizure prediction utilising human-derived induced pluripotent stem cells and human ion channel assays

sezureposter2 | ApconiX

Development of a human derived induced pluripotent stem cell neuronal assay for early in vitro detection of seizure liability

A balance between inhibitory neurotransmission and neuronal excitation is critical for normal brain function. At the simplest level, seizures occur when this balance is disrupted, resulting in increased or decreased activity.

Seizures are life-threatening events and therefore serious drug-induced adverse events. The occurrence of seizure can negatively impact a drug discovery project.

Issues with drug safety and toxicity are a leading cause of attrition. After the cardiovascular system, adverse events in the Central Nervous System (CNS) are the second most common source of attrition. CNS-related issues account for nearly a quarter of failures during clinical development, a phase where consequences are high in terms of resources and patient impact. Current methods for seizure detection rely on the nonclinical rodent and non-rodent studies required to support clinical trials. This illustrates a need for better human-based methods of preclinical seizure detection.

We have developed two novel in vitro assays that provide an integrated approach to early seizure liability screening:

  1. A panel of 15 ion channels that can be screened using automated electrophysiology
  2. A microelectrode array assay that utilises human-derived neuronal stem cells to demonstrate potential seizure activity by measuring electrical activity

This approach allows exploration of compound effects on both the molecular ion channel level, and more holistically across a neuronal network.

NAMs are novel alternative methods. NAMs broadly encompass approaches that aim to refine in vivo methods or improve in vitro testing. This includes 3D tissue culture models and the use of computational methods, such as machine learning. There is increasing interest in NAMs to improve predictivity of human safety risks, including detection of seizure liability.

Our human ion channel assay coupled with assessment of electrical activity in hiPSC neuronal cells has been highlighted by the FDA/CDER as a useful NAM that should be considered as a component of the overall safety assessment for seizure liability.

MEA enables high-throughput non-invasive measurement of electrical activity from a network of heterogenous neuronal cells. This has great potential for predicting seizure liability of drug candidates as changes in neuronal firing can be measured in real-time with millisecond temporal resolution using specialised plates with electrodes. This allows for analysis of multiple parameters that illustrate the activity of neuronal networks.

MEA FAQ | ApconiX

We have identified 15 ion channels with a link to seizure, based on genetic and pharmacological evidence.  All are human isoforms: Nav1.1, Nav1.2, Nav1.6, Kv1.1, Kv2.1, Kv3.1, Kv4.2, KCa1.1, KCa4.1, Kv7.2/7.3, Kv7.3/7.5, GABA α1β2γ2, NMDA 1/2A, nicotinic AChR α4β2, Cav2.1

2-3mg is required for the ion channel panel, and 5mg is required for the MEA assay.

Ion channel panel data is reported within 2 weeks of ApconiX receiving the test items. The MEA experiment and data analysis takes about 7-8 weeks in total.

The ion channel panel can be deployed when a client has identified a seizure risk and is keen to gain a mechanistic insight. Or, the ion channel panel can be run alongside other secondary pharmacology assays to identify possible hazards. The MEA assay can be deployed when the client wishes to prioritise candidates ahead of in vivo studies, or to understand species relevance.

Our group has published a number of papers and opinion pieces on this subject: Roberts et al. (2021) Toxicol. Sci. 179: 3-13, and Rockley et al (2019) Toxicol. Res. 8: 784-788

This work was completed by a Post Doc in our lab, Kimberly Rockley. Kim has won a number of awards for this work, including Bionow Rising Star Award, and Society of Toxicology Best Poster Award in the in vitro and alternative methods Speciality Section. More of Kim’s posters can be seen here.

Want to find out more?

To discuss the best approach for your drug project, please get in touch.