Refining neurovascular in vitro models

All systemically administrated drugs need to be evaluated for central nervous systems (CNS) penetration and adverse effects.

Unfortunately, and especially for new drug modalities, the pre-clinical methods of pharmacokinetics (PK) and pharmacodynamics (PD) for the CNS show low translation to humans.

Here, we focus on developing and validating human functional in vitro models of the neurovascular unit (NVU) to use when the current non-CNS cell lines fail to predict human CNS responses.

This will mitigate the increased animal use for new drug modalities and pave the way for decreased and refined animal models for CNS PK and toxicity.

We will use our protocols for induced pluripotent cell-derived cells (endothelial cells, astrocytes, microglia, pericytes, and neurons) in microfluidic systems as a physiological model of the NVU, a NVU-on-chip. The NVU-on-chips are formatted and optimized to be applicable in pharmaceutical settings.

Our validations include tool compounds and AstraZeneca in-house compounds for drug penetration and drug-drug interactions. Next, we will evaluate adverse effects in the NVU post-drug administration.

Finally, the most innovative part of this proposal is that we will use the NVU-on-chip to evaluate NVU penetration and adverse effects of new drug modalities, including viral vectors, nucleotide-based drugs, and peptide/protein-based drugs. Several of these drug modalities are human or organ-specific, which motivates the need for human functional NVU models.