All pharmaceutical development programs carry a certain amount of risk. However, when it comes to developing drugs that target the central nervous system, the odds of success narrow significantly.
Drugs that pass the blood-brain barrier are at greater risk of producing neurotoxic effects. As a result, the use of robust in vitro and in vivo models to build an early understanding of neurotoxic potential is essential. However, current trends in attrition rates and the ongoing withdrawal of the industry from neuroscience research highlight the need for better preclinical models of neurotoxicity.
Read on to find out how human iPSC-derived cortical neurons are playing a key role in developing more translationally useful neurotoxicity models that could help to reduce attrition in drug development.
What is neurotoxicity?
Neurotoxicity refers to any adverse effect on the structure or function of the central nervous system, caused by exposure to a biological, chemical or physical agent. These substances, known as neurotoxins, alter the normal function of the nervous system by causing permanent or reversible damage to nervous tissue.
At the greatest risk from the damaging effects of neurotoxins are neurons, due to their high rate of renewal. However, other key components of nerve tissue, such as oligodendrocytes, astrocytes, microglia and capillary endothelium cells can also experience neurotoxin damage .
A wide range of natural and man-made substances can cause neurotoxic effects in humans, including therapeutic drugs, drugs of abuse, insecticides and pesticides, cosmetics, certain foods and food additives as well as industrial chemicals such as cleaning solvents. For this reason, global regulatory bodies require a comprehensive understanding of neurotoxicity before products can be tested in humans and released to the market.
The current state of neurotoxicity research
Given their greater potential for causing neurotoxic damage, developing drugs that target the central nervous system can be particularly challenging, and often carry a much greater risk of late stage development failure.
Indeed, organ specific toxicity in the central nervous system accounts for 7 percent of preclinical drug safety failures and 34 percent of clinical failures . The same study found that compound related off target effects identified during preclinical testing contribute to three quarters of development project failures. These statistics highlight the underlying challenge of recognizing neurotoxicity in the preclinical stage using current in vitro and animal models. As a result, unsuitable drugs are progressing into the clinical development phase, where the financial cost associated with program failure is significantly higher.
Because of the higher risk, cost and complexity associated with central nervous system drug development, many major pharmaceutical companies have scaled back their neuroscience research efforts in recent years. However, with growing demand for innovative therapies for neurodegenerative disorders such as Alzheimer's and Parkinson's disease, these decisions come at a significant cost to patient health.
These current trends highlight the urgent need to improve the predictive capabilities of neurotoxicity models. Specifically, the translatability and sensitivity of these in vitro models must be improved to enhance usefulness for neurotoxicity screening. Supporting this goal, there is also a need to better identify early toxicity biomarkers to successfully predict neurotoxicity at the earliest stages of development.
The search for more translationally viable neurotoxicity models
One organization working to develop better models of neurotoxicity is the Health and Environmental Science Institute (HESI) . By actively facilitating scientific collaboration, they hope to advance our understanding of early neurotoxicity mechanisms and biomarkers, as well as increase the translation and sensitivity of predictive models.
New research forming part of the HESI collaboration is focused on evaluating whether seizurogenic activity, studied using high-throughput multi-electrode array (MEA) technology, can be used as an indicator to better predict neurotoxicity in human stem cell-derived neurons. Using Axol's human iPSC-derived cortical neurons as a robust cell preparation for their studies, Odawara and colleagues recently characterized the dynamics of seizurogenic activity in response to convulsant drugs .
Raster plots and array-wide spike detection rate (AWDR spikes/100ms) in the same well. 4-AP (0, 0.3, 1, 3, 10, 30 μM). Pilocarpine (0,0.3, 1, 3, 10, 30 μM). chlorpromazine (0, 0.1, 0.3, 1, 3, 10 μM). PTZ (0, 1, 10, 100, 1000 μM).
The studies found that four convulsant drugs (4-aminopyridine, pilocarpine, chlorpromazine and pentylenetetrazole) increased synchronized burst firing of the human iPSC-derived cortical neurons, each provoking a unique firing response. These results highlight the potential of high-throughput MEA and iPSC-derived neurons as a highly sensitive and translationally useful method for neuronal toxicity drug screening.
Axol provide high-quality tools for toxicity prediction to improve translation from in vitro to in vivo and reduce failure rates in late stage preclinical safety testing.
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