Improving Physiological Relevance in Neurological Disease Drug Development

Elise Malavasi, Ph.D., is a Principal Scientist at Concept Life Sciences, a leading contract research organisation, where she specialises in the development and use of in vitro assays for neurobiological research. Of particular interest to Elise is the development of functional assays for microglia, a cell type that is increasingly viewed as a therapeutic target in neurodegenerative disease. To support drug development, these assays would need to be amenable to long-term use, meaning it is crucial that the cells used show lot-to-lot consistency. Such consistency has been challenging to develop with primary cell lines, and from human induced pluripotent stem cell (hiPSC) derived cells generated using directed differentiation. Therefore, Elise and her colleagues have partnered with bit.bio to test the utility of ioMicroglia* in their functional assays. They’ve found bit.bio’s cells to be highly functional and, critically, to have lot-tolot consistency. Elise’s team is now exploring the use of ioMicroglia in more complex model systems. This work opens the door for Concept Life Sciences to offer more human-relevant models to their clients and better support CNS-targeted drug development. bit.bio case study Elise Malavasi, Ph.D, Principal Scientist, Concept Life Sciences The need for a predictable, physiologically relevant human microglia in neuroscience drug development “Given the attrition rates in neuroscience drug development, advances in the quality and reliability of human induced pluripotent stem cells could be transformative for the pharmaceutical industry,” explains Elise Malavasi, Ph.D., an expert in the development of in vitro assays for applications in neurobiological research. Elise serves as Principal Scientist in the neuroscience division at Concept Life Sciences—a leading contract research organisation serving the pharmaceutical, biotech and agrochemical industries—where she is acutely aware of the industry’s need for better preclinical models and the promise of human induced pluripotent stem cell (hiPSC)-derived cells. Approximately 97% of CNS-targeted drug candidates entering phase 1 clinical trials will never make it to market¹, with some disease-specific therapeutics nearing 100% failure². Such a low success rate is due, in part, to the low predictive validity of preclinical models, many of which rely on non-human or immortalised cell lines—models which often fail to recreate key genetic and physiological features of human disease³. “Having a human model system that behaves predictably is crucial,” emphasises Elise. Improving physiological relevance in neurological disease drug development Stages of the drug discovery pipleine supported by Concept Life Sciences. Image courtesy of Concept Life Sciences. DISCOVERY PROCESS BIOLOGY CHEMISTRY ADME / DMPK “ioMicroglia from bit.bio offered a solution by providing consistent and reproducible human iPSC-derived microglial cells” bit.bio case study Elise Malavasi, Ph.D, Principal Scientist, Concept Life Sciences However, building human models of the CNS is a difficult task, not least of all because primary human neurons and glial cells are in short supply. As a result, the scale and clinical relevance of compound screening is greatly limited. Researchers like Elise are looking to change this through the use of hiPSC-derived cells. “For neuroscientists in particular,” she explains, ”hiPSC-derived cells are interesting because they give you access to human cell types and disease-relevant phenotypes that have previously been hard to come by.” Elise’s team recently set out to develop assays that can be used to assess a drug candidate’s effect on human microglia. These brain resident immune cells are increasingly recognised as having a role in neurodegeneration and have become common targets in drug development pipelines. Therefore, many of Concept Life Sciences’ clients are likely to need reliable and scalable models that use human microglial cell lines. “We use microglia in our assays to understand the effects of compounds on microglial functions, ranging from inflammatory cytokine response following activation, to other functional responses like phagocytosis and migration,” explains Elise. While efficient derivation of microglia-like cells from human pluripotent stem cells is possible, current protocols lack the scale and robustness that’s needed for drug development applications. “ioMicroglia from bit.bio offered a solution by providing consistent human iPSC-derived microglial cells,” says Elise. Accessing consistent human iPSC-derived microglia at scale ioMicroglia are defined human microglial cells generated from iPSCs using bit.bio’s opti-ox* precision cell reprogramming technology. Opti-ox is a gene engineering approach that uses dual genome-safe harbour targeting to achieve precise control over cell-fatedefining transcription factor expression while protecting the integrity of the cell and avoiding gene silencing. As every iPSC in the population is powered by opti-ox, entire iPSC populations can be consistently converted into functional microglia at scale. “One of our recent aims has been the optimisation of microglial phagocytosis assays, and we have successfully used ioMicroglia to test the effect of different pro- and anti-inflammatory stimuli on the cells’ phagocytic activity,” says Elise. “A key advantage of ioMicroglia for us is the low inter-lot variability, which ensures consistent assay performance and facilitates longterm, and large-scale screening studies. Consequently, we can now screen multiple compounds over extended periods and be confident in the reliability and reproducibility of our findings.” With a consistent and scalable source of functional human microglia, Concept Life Sciences now has the potential to build more complex, human-relevant models for its clients. “We’re excited about the possibility of collaborating with bit.bio on this further to explore other assays, including microglia cytokine release and microglia activation