Accelerating drug discovery by early assessment of neurotoxicity

We understand the importance of knowing whether your compounds adversely affect the structure, function, or chemistry of the nervous system. With this in mind, we offer a front-loaded approach to neurotoxicity testing where our validated high-capacity in vitro models are applied for early-stage neurotoxicity evaluations, with the goal to save time and money for our Clients.

Physiological relevance

Gain access to well-established assays based on complex in vitro neuronal cultures.

High-capacity

Our high-capacity platform facilitates early-stage neurotoxicity evaluations across a broad range of readouts.

Cost-efficient

Early-stage neurotoxicity evaluations to minimize risk for costly in vivo tox findings and clinical failures.

Neurotoxicity evaluation in vitro

We are offering assessment of both acute and chronic toxicity in complex neuronal cultures, to enable efficient toxicity evaluations early in the discovery process with the aim to minimize risk for subsequent in vivo toxicity findings or clinical failures.

At Cellectricon, we have developed a neurotoxicity offering that is based on several of our already validated models originally developed for target and lead discovery programs. While simpler in structure, in vitro models still recapitulate key features of the brain such as cellular diversity and connectivity – as evidenced in our labs for example by appropriate pharmacological responses to known drugs of synaptic communication between cortical neurons and an altered cytokine release profile from microglia¹^,².

Furthermore, we have been able to demonstrate an extremely good correlation between the effect on neuronal function in our acute neurotoxicity model with published in vivo data³^, ⁴. Although originally applied to assess the putative toxic effects of oligonucleotide-based drugs before in vivo studies, such as ASOs and siRNAs, our neurotoxicity screening services have now expanded to all modalities.

Jonna Sjöholm
Lab Manager

We can assess neurotoxicity across a broad range of cellular mechanisms

“Our validated models were developed for target- and lead discovery applications and are used for disease-modeling in e.g. neuropsychiatry and neuroinflammation. In addition to central neuronal models, we have long experience in creating models of peripheral neuropathies, including chemotherapy-induced peripheral neuropathy (CIPN).”

Our neurotoxicity testing capabilities

Building on our long experience from developing advanced in vitro models for target- and lead discovery applications, we have created a broad range of sensitive and relevant assays suitable for neurotoxicity evaluations.

Our neurotoxicity screening services support the development of safe therapeutics by offering access to predictive, high-capacity in vitro assays that can be applied early in the drug discovery process. The services combine advanced primary and stem cell cultures with a broad range of readouts to enable assessment of both acute and chronic toxicity in complex neuronal cultures.

Our services include a suite of assays for assessing drug effects on e.g. neuronal function, cellular phenotype, and the immune response. Since the technologies employed are designed for high-capacity applications, we enable efficient toxicity evaluations early in the discovery process to minimize risk for in vivo tox findings and clinical failures. Our offering is including the following read-outs:

Neuronal excitability – Optical electrophysiology-based readout for detection of alterations in neuronal excitability, e.g. hyperexcitability stemming from CIPN.

Cytokine release – Cytokine and chemokine release from neuroinflammation tri-culture models for assessment of chronic neuroinflammatory toxicity.

Neurite outgrowth – Assessment of chronic and direct neurotoxicity using single cell neurite outgrowth assays.

Cellular phenotype – Multiparametric high content imaging-based assessment of cellular phenotypes for detection of global or cell type-specific toxicity.

Neuronal function – Optical electrophysiology-based readout for assessment of acute neurotoxicity from oligonucleotides or compounds with seizure-liability.

Metabolic activity & damage markers – Readouts from primary- or iPSC-derived cultures for assessment of toxicity by quantification of metabolic activity or damage markers, such as ATP or LDH.

Evaluating chronic and acute toxicity effects on neuronal function

Using our proprietary optical electrophysiology platform, we can assess how a compound affects spontaneous and evoked neuronal activity and excitability. The acute effects of adding test molecules are assessed on population level in a high-capacity manner from synaptically connected neuronal cultures and quantified as changes in neuronal calcium influx. For more detailed follow-on studies, the label-free technology high-density multielectrode array (MEA) technology can be applied.

Neuroinflammation model to determine effects on cytokine and chemokine release

We have developed several neuroinflammation models, based on rodent cortical cultures or human iPSC-derived microglia co-cultures. These cultures encompass neurons, astrocytes and microglia in resting state. Here, large-scale profiling of e.g. cytokines and other proteins relevant for neuroinflammation are assessed using the Luminex platform. For toxicity assessment, the effect of chronic treatment on microglia activation, and subsequent cytokine and chemokine release is quantified.

High-capacity compartmentalized systems for assessment of CIPN

We have developed a microfluidic high-capacity compartmentalized cell culture platform, that can be used to separate axons from cell bodies, as well as for the creation of co-culture systems comprised of peripheral sensory neurons and spinal cord neurons. This can be employed in combination with optical electrophysiology to assess side effects, such as chemotherapy-induced peripheral neuropathy, by quantifying the neuronal excitability in the peripheral sensory neurons, the effect on synaptic connectivity between these and the spinal cord neurons, and in addition assess the neurite outgrowth from the dorsal root ganglia.

Paul Karila
CBO

Our assays are developed and validated in collaboration with our Clients

“We have developed a range of high-quality in vitro models which have been validated with industry Clients. Our models reflect either developmental or adult neurotoxicity, and acute as well as delayed-onset toxicity. We have validated the usefulness of these models with our valued Clients with an initial focus on oligonucleotide-based drugs.”

Case studies

Our Neurotoxicity Testing Services is based on several of our already validated models originally developed for target and lead discovery programs. Originally applied to assess the putative toxic effects of oligonucleotide-based drugs before in vivo studies, such as ASOs and siRNAs⁴, our neurotoxicity screening services have now expanded to all modalities. The high-capacity format facilitates early-stage neurotoxicity evaluations, with the goal to save time and money for our Clients.

Download Case Study (PDF)

References

1. R. NEFF1, C. LINDWALLBLOM2, Å. JÄGERVALL2, B. BALANA1, M. KARLSSON2, P. KARILA2, T. LOVENBERG1;
1 Neurosci. Drug Discovery, Janssen Res. and Develop., San Diego, CA; 2 Cellectricon AB, Mölndal, Sweden. Development of a moderate throughput assay to detect novel modulators of synaptic efficacy in neuronal cultures. Program No. 209.10. 2015 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2015. Online.

2. L. AGHOLME1, A. SKILJE1, C. NODIN1, B. MA2, M. KARLSSON1, J. PIHL1, J. M. LEVENSON2;
1 Cellectricon AB, Mölndal, Sweden; 2 FireCyte Therapeut., Beverly, MA. Validation os a Systems Biology Platform for Neuroinflammation with Benchmark Pharmacological Agents. Program No. PSTR455.19. 2024 Neuroscience Meeting Planner. Chicago, IL. : Society for Neuroscience, 2024. Online.

3. Hagedorn, P. H.; Brown, J. M.; Easton, A.; Pierdomenico, M.; Jones, K.; Olson, R. E.; Mercer, S. E.; Li, D.; Loy, J.; Høg, A. M.; Jensen, M. L.; Gill, M.; Cacace, A. M. Acute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features. Nucleic Acid Therapeutics 2022, 32 (3), 151–162. https://doi.org/10.1089/nat.2021.0071.

4. C. Nodin1, J. Sjöholm1, Y. Li2, T. Barbour2, J. Pihl1, P. Karila1, F. Touti2, D. Eyerman2;
1 Cellectricon AB, Mölndal, Sweden; 2 Apellis Pharmaceuticals, Boston, MA, USA. Detection of acute and delayed onset toxicity effects of ASOs using in vitro neuronal models. POster @ oligonucleotides for CNS Summit. boston, Ma, USA, 2025. online.