Use of Human Stem Cell Models of Neurological Disease to Advance Drug Discovery

Drug discovery programs require a robust panel of models and assays to identify and validate drug targets, support compound optimisation, and run mechanistic studies. Fully human in vitro model systems comprising iPSC-derived neurons and/or glia represent robust and flexible systems to provide translationally relevant data and support decision making. Complexity can be built using multi-culture systems comprising multiple cell types and/or by working in 3D.

Use of patient-derived iPSCs harbouring autosomal dominant mutations (e.g. APP and PSEN1 mutations causal for monogenic Alzheimer’s disease, AD) enable cellular dysfunction underlying disease pathogenesis to be studied and exploited. Cellular phenotypes including altered b-amyloid ratios and endolysosomal dysfunction can be studied in human monogenic AD iPSC-derived neurons.

In addition to neuronal dysfunction, glia are increasingly being recognised as important players in neurological disease. Genetic associations between multiple immune genes and risk of developing AD highlight the role of neuroinflammation in disease pathogenesis. We have generated a fully human iPSC-derived cortical neuron-microglia coculture system to enable mechanistic studies of neuroinflammation, suitable for neuroinflammation target identification, validation and compound profiling. Microglia display both homeostatic and damage response behaviours in coculture, are phagocytically active and release cytokines in response to proinflammatory stimulation.

Human iPSC-derived neuronal and glial models comprising multiple cell types and/or patient-derived cells capture relevant neurodegenerative and neuroinflammatory outcomes, enabling generation of translationally relevant data to advance drug discovery.

Learning Objectives: 

1. Review how stem cell models of neurological disease can be used to support drug discovery.

2. Demonstrate knowledge on how cellular phenotypes can be studied in monogenic Alzheimer’s disease neurons.

3. Demonstrate knowledge on how neuron-microglia cocultures can be used to study neuroinflammation.