There are 90% of failure in clinical trials, mainly due to safety and efficiency issues. In particular, the central nervous system is involved in 34% of failure in clinical trials, but only in 7% of failure in preclinical trials (Cook et al., 2014). That points a lack of relevance in preclinical models, including in vitro models used to select drug candidates. Therefore, the aim of Veronique De Conto‘s thesis in HCS Pharma, under the supervision of Vincent Berezowski (Inserm unit 1171), is to develop more relevant cerebral in vitro models, to better select candidates in early stages of drug discovery process.
In this context, Veronique is working on two projects: the development of a cerebral in vitro model for neurotoxicity assessment, and the development of an in vitro model in 3 dimensions for drug discovery in Parkinson’s disease.
In the first project, she studied the impact of differentiation method on the characteristics of SH-SY5Y cell line. Indeed, SH-SY5Y cells are commonly used by the pharmaceutical industry for neurotoxicity assessment, and many methods can be used to differentiate these cells into neurons (Xicoy et al., 2017). She compared them to select an efficient and reproducible method, based on the assessment by HCS of cell proliferation, neurite outgrowth, neuronal marker expression and sensitivity to neurotoxic compounds. She performed these tests in 2D and 3D cultures.
In the second part, she studied the impact of matricial and cellular microenvironment on Luhmes cells (dopaminergic neuronal cell line), in collaboration with Dr David Devos‘ team. First she screened 1 280 molecules in Luhmes cell cultivated in 2D with an inducer of Parkinson’s disease, to identify some neuroprotective molecules. Then she cultivated these cells in BIOMIMESYS® Brain, a hyaluronic acid-based hydroscaffold that mimics the extracellular matrix, in order to improve the relevance of the model by including the microenvironment. She studied the impact of matricial microenvironment on cell viability and neuronal differentiation. Now she is testing a co-culture of Luhmes cell with astrocytes in BIOMIMESYS® Brain, because astrocyte are also involved in Parkinson’s disease, via neuro-inflammatory reaction.
Cook, D., Brown, D., Alexander, R., March, R., Morgan, P., Satterthwaite, G., and Pangalos, M.N. (2014). Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nat Rev Drug Discov 13, 419–431.
Xicoy, H., Wieringa, B., and Martens, G.J.M. (2017). The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener 12.