Before approval for use, chemicals and pharmaceuticals must be tested to predict the likelihood that they will cause toxicity to the nervous system. Owing to the complexity of the human central nervous system, predicting neurotoxicity can be difficult. At present animal research is often used to determine neurotoxic effects, but research indicates that a human tissue approach carried out in vitro might more closely model neurotoxicity in humans.
The team led by Dr Jos Joore from MIMETAS BV, have convincingly developed proof-of-concept for a novel microfluidic neurotoxicity screening platform, designated NeuroScreen-3D in OrganoPlates®. The platform contains mixed populations of human induced pluripotent stem cell-derived (iPSC) neurons in a high-throughput microtiter plate format delivering 96 data points. NeuroScreen-3D fully supports neurotoxicity screening with integration of functional, morphological as well as electrophysiological endpoints. During Phase 1, they have demonstrated that mixed populations of mature human iPSC neurons in NeuroScreen-3D recapitulate neuronal function and network activity, including the detection of spontaneous neuronal calcium transients. Functionality of NeuroScreen-3D was further demonstrated by concentration-dependent reduction of neuronal viability following exposure to neurotoxicants. Using multielectrode array (MEA) recordings, it was shown that iPSC neurons become spontaneously active and are sensitive to modulation by physiological, pharmacological and toxicological agents.
In Phase 2, MEAs will be integrated in OrganoPlates® for assessment of neuronal toxicity and function in 3D cultures using both electrophysiology and high-content imaging. Validation and in vitro-in vivo extrapolation of NeuroScreen-3D will be performed in close dialogue with the Sponsor/s using a reference set of (non-) seizurogenic and/or neurotoxic compounds. NeuroScreen-3D will be commercialised as a cost-effective and user-friendly in vitro neurotoxicity screening platform, replacing currently used ex vivo hippocampal slice and neurobehavioral assays. In this way, NeuroScreen-3D aims to reduce animal experiments significantly, while delivering more accurate predictions of potential adverse effect in humans to improve clinical development success.
Full details about this CRACK IT Challenge can be found on the CRACK IT website.
Tukker AM et al. (2018). Human iPSC-derived neuronal models for in vitro neurotoxicity assessment. NeuroToxicology, doi.org/10.1016/j.neuro.2018.06.007.
Wevers NR et al. (2016). High-throughput compound evaluation on 3D networks of neurons and glia in a microfluidic platform. Scientific Reports 6, Article number: 38856 (2016). doi:10.1038/srep38856.
Tukker AM et al. (2016). Is the time right for in vitro neurotoxicity testing using human iPSC-derived neurons? ALTEX 33, 261-271 doi: 10.14573/altex.1510091.
Contractor(s)Dr Jos Joore