In vitro assessment of chemotherapy-induced neuronal toxicity.

ABSTRACT

Neurotoxicity is a major concern during drug development, and together with liver and cardio-toxicity, it is one of the main causes of clinical drug attrition. Current pre-clinical models may not sufficiently identify and predict the risk for central or peripheral nervous system toxicity. One such example is clinically dose-limiting neuropathic effects after the administration of chemotherapeutic agents. Thus, the need to establish novel in vitro tools to evaluate the risk of neurotoxicities, such as neuropathy, remains unmet in drug discovery. Though in vitro studies have been conducted using primary and immortalized cell lines, some limitations include the utility for higher throughput methodologies, method reproducibility, and species extrapolation. As a novel alternative, human induced-pluripotent stem cell (iPSC)-derived neurons appear promising for testing new drug candidates. These iPSC-derived neurons are readily available and can be manipulated as required. Here, we describe a novel approach to assess neurotoxicity caused by different classes of chemotherapeutics using kinetic monitoring of neurite dynamic changes and apoptosis in human iPSC-neurons. These studies show promising changes in neurite dynamics in response to clinical inducers of neuropathy, as well as the ability to rank-order and gather mechanistic insight into class-specific compound induced neurotoxicity. This platform can be utilized in early drug development, as part of a weight of evidence approach, to screen drug candidates, and potentially reduce clinical attrition due to neurotoxicity.