Hi Sejal.
Developing a reliable and translatable in vitro blood–brain barrier (BBB) model is a desire for advancing drug development in CNS. So thank you for this question.
Species differences is major hurdle in translating experimental therapeutics from the research laboratory to the clinic, and while traditional in vitro models can replicate essential features of drug transport across the BB), they do not fully represent in vivo CNS uptake. High-end human BBB models created using microfluidic technologies offer insights into transport and BBB homeostasis, but complexity doesn't always translate to better applicability.
There's no one-size-fits-all BBB model and identifying critical components for recapitulating BBB function remains uncertain. Using stage appropriate models, it may be possible to improve the predictive capacity in benchmarking candidate therapeutics. Hence, improving our ability to model the BBB with physiological accuracy in relatively simple in vitro models is critical for the development of new CNS therapies.
As our knowledge of the in vivo BBB increases, we need to continue to advance the phenotype and reproducibility of in vitro BBB models.
Regarding in-silico models, both graph neural networks-based deep learning models and conventional physicochemical-based machine learning models have demonstrated comparable performance. These models exhibit usefulness in the early drug discovery process, allowing compounds to be ranked at the top of the screening funnel.
Look forward to comments/insight from experts in this area.
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Pankajini Mallick PhD
Principal Scientist, Preclinical Pharmacokinetics | Modeling and Simulation
San Diego CA
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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Original Message:
Sent: 04-19-2024 11:50
From: Sejal Sharma
Subject: Blood brain barrier drug transport
In drug development and neurological research, the permeability of substances across the blood-brain barrier (BBB) is crucial for predicting their efficacy and safety in vivo. Brain endothelial cell uptake studies are commonly employed in vitro to assess BBB permeability. However, the reliability of these studies in predicting in vivo brain uptake remains uncertain.
Recent advancements have introduced more complex in vitro models, including co-cultures and tri-cultures incorporating brain endothelial cells along with astrocytes and neurons, aiming to better mimic the neurovascular unit and improve predictive capabilities. How do these advanced in vitro models compare to traditional brain endothelial cell uptake studies in predicting BBB permeability and in vivo brain uptake? Additionally, if present what types of in silico predictions are available to reflect the accuracy of these permeability predictions?
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Sejal Sharma
Research Assitant
Texas Tech University Health Sciences Center
Amarillo TX
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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