SOT 64th Annual Meeting and ToxExpo
March 16-20, 2025 | Orlando, FL
Join AxoSim at SOT 2025 – Booth #1310!
We’re heading to the Society of Toxicology (SOT) Annual Conference & ToxExpo, and we can’t wait to connect! Visit booth #1310 to discover how AxoSim’s human-relevant 3D neuro models can improve CNS and PNS drug development pipelines. Schedule a meeting in advance to ensure dedicated time with our experts.
A nondestructive, image-based cytotoxicity assessment for combined safety and efficacy screening in human-iPSC derived organoids.
Abstract Number/Poster Board number
4632/J468
Session Date and Time
3/19/2025 1:45 PM - 4:15 PM
Abstract
Drug development pipelines utilize many complimentary biochemical, cell-based, in vitro and in vivo assays, each of which provides a limited amount of safety or efficacy data. Assay development and validation take valuable time and drive-up preclinical development costs. Furthermore, data from disparate sources must be combined to select the optimal drug candidates to pursue, an operation frequently plagued by inconsistencies between assays (e.g. cell types, media conditions, endpoints). A single complex in vitro model (CIVM) that combines both safety and efficacy testing offers many advantages over the traditional approach of using separate models. We previously developed a human induced pluripotent stem cell (iPSC)-derived neural organoid system to model CDKL5-deficiency disorder (CDD), which provides a system by which to test for drug efficacy in reducing a neuronal hyperexcitability phenotype (Negraes et al., Mol. Psych. 2021). This model recapitulates key functional features of CDD, a rare X-linked neurodevelopmental disorder characterized by early onset seizures, developmental delay, and severe intellectual disability. While this model was used to identify promising drug candidates, the safety profile and relative safety margins of the proposed drugs were unknown. Gold-standard ATP-based viability assays provide safety information at the end of a drug treatment but are destructive in nature and sacrifice valuable biological samples for a single data point. Longitudinal assays based on membrane rupture and release of cellular components provide a non-destructive means to monitor cell health but can become costly and time-intensive if performed over the course of weeks and still require perturbation of the experimental system (i.e. collecting media). Here, we sought to develop a non-invasive image-based viability assay that would enable monitoring of CDD patient-derived neural organoids and utilize the combined safety and efficacy data to identify potential safe and effective CDD therapeutics.
Comparison of a 3D Nerve-on-a-Chip peripheral nerve model to 2D neuronal assays for clinical translation with antibody-drug conjugate (ADC) toxicity screening.
Abstract Number/Poster Board number
4626/J462
Session Date and Time
3/19/2025 1:45 PM - 4:15 PM
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of anticancer therapies, often resulting in chronic pain and loss of sensation as peripheral sensory and motor neurons degenerate from chemotherapy exposure. CIPN ranges in severity from mild annoyance through life-threatening and is a leading cause for patients to switch or discontinue treatments. Depending on the compound, CIPN can be detected with preclinical testing using either 2D cell culture or animal models early in the drug development pipeline before human clinical testing. However, many compounds have passed preclinical testing demonstrating minimal toxicity but were found to cause peripheral neuropathy and other side effects in clinical testing, leading to low clinical trial success rates and limited use of approved compounds. Antibody-drug conjugates (ADCs), highly toxic payloads linked to tumor-specific monoclonal antibodies, are a recent example of compounds designed to have excellent specificity through preclinical testing but unfortunately have shown unexpected peripheral neuropathy in patients. A more predictive human pre-clinical model therefore would significantly reduce the cost and risk of preclinical testing and thereby accelerate the drug discovery process. Microphysiological systems (MPS) offer a promising alternative, bridging the gap between 2D cell cultures and human clinical data by providing an in vitro model with in vivo-like characteristics. We have developed an MPS incorporating human iPSC-derived sensory neurons and human primary Schwann cells to assess toxicity in 2D and 3D formats. The 2D platform uses imaging-based readouts to detect toxicity independently for sensory neurons and Schwann cells. The 3D platform creates a 3D Nerve-on-a-Chip, or NerveSim®, by guiding axonal growth down a channel over an embedded electrode array (EEA) in custom-designed 24-well tissue culture plates. The 3D cultures can deliver functional electrophysiology using the EEA to stimulate and record from 10 locations along the nerve, combined with non-invasive brightfield imaging to track morphology over time. Here, we used both platforms to test and compare the in vitro toxicity of 4 ADCs as well as the common ADC payload monomethyl auristatin E (MMAE).
Improving the stability and reproducibility of clinical neurotoxicity predictions from a high-throughput compatible neural organoid platform.
Abstract Number/Poster Board number
4633/ J469
Session Date and Time
3/19/2025 1:45 PM - 4:15 PM
Abstract
The drug development process is fraught with failure due to either safety issues or poor efficacy. When considering safety profile, neurotoxicity is the leading cause of clinical failure (Cook et al., Nat. Rev. Drug Disc., 2014). Furthermore, 12% of drugs withdrawn between 1960-1999 were caused by neuroliabilities (Valentine & Hammond, J. Pharmacol. Toxicol. 2009). The use of complex in vitro models (CIVM) derived from human tissue has dramatically expanded in recent years, promising to provide the necessary biological complexity to improve clinical translation and scale to enable adoption early in drug development pipelines. However, few of these CIVMs have been rigorously tested in terms of their predictive abilities or stability of these predictions over time (reviewed by Kang et al., Biofabrication 2024). Towards this end, we have developed a human induced pluripotent stem cell (iPSC)-derived cortical organoid platform, amenable to high-throughput screening (HTS) on a multiparametric functional endpoint. The functional “waveform” activity in these neural organoids can be reproducibly modified with excitatory and inhibitory modulators, confirming the presence of a fully functional integrated glutamatergic / GABAergic circuitry, ultimately providing a unique high-throughput and translatable drug screening alternative to the traditional pre-clinical screening model. In 2022, this organoid platform was used to develop a predictive clinical neurotoxicity model that showed remarkable specificity (>90%) and good sensitivity (>50%), making it an ideal pre-screening method prior to standard 2-species animal testing (Wang et al., ALTEX 2022). Here, we tested the stability and reproducibility of these predictions over time and used these replicate experiments to refine and automate neurotoxicity score predictions.
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