The complex interplay between neurons and microvessels responsible for the coupling of brain activity and blood supply to the brain requires an integrated, functional unit, termed the ‘neurovascular unit’ (NVU). The composition of the NVU varies with vessel size, but typically includes capillary endothelial cells, neurons, astrocytes, pericytes and extracellular matrix components. In addition to ensuring neurovascular coupling, the NVU provides the first line of defence against the detrimental effects of potentially neurotoxic molecules and cells in the systemic circulation. The barrier between blood and nervous tissues is evident at multiple interfaces; the best described being the cerebrovascular blood-brain barrier (BBB). The barrier arises from the specialized capillary endothelial cells of the NVU, which differ from peripheral endothelial cells in that they are not fenestrated, they have minimal pinocytotic activity, very low rates of transcytosis, express drug efflux transporters and are coupled by tight junctions (TJ). The properties of the endothelium therefore also represent the primary barrier for the transport of drugs across the BBB, and is crucial in maintaining the homeostasis of the brain’s microenvironment. The other cells of the NVU may help maintain the barrier properties of endothelial cells and may also directly be involved in the barrier.
Most molecules and especially biologics do not cross the BBB and this is therefore a critical factor limiting the future application of neurotherapeutics. However, the need to develop CNS-active agents for neurological disorders including dementia or multiple sclerosis is greater than ever. This will require a more comprehensive understanding of BBB transport mechanisms and targets that could facilitate brain delivery. Recently, new opportunities for brain specific delivery of biologics have arisen. Challenging Receptor Mediated Transcytosis (RMT) and Carrier Mediated Transcytosis (CMT) with specific antibodies and peptides along with several drug delivery systems (including liposomes, nanoparticles, exosomes) or viral delivery agents have shown to deliver biopharmaceuticals into the CNS. Due to the lack of understanding of fundamental biological processes enabling the translocation of macromolecules or viruses through the BBB, the breakthrough of clinically relevant brain delivery approaches is still waiting to arise.
The overall goal of the IM2PACT consortium is to address critical gaps in the field by comprehensively investigating the molecular and cellular properties of the BBB in human patient material, cutting-edge human in vitro models and in vivo preclinical models in order to understand BBB transport mechanisms and identify new BBB targets for brain delivery in health and disease. IM2PACT will robustly validate the models by establishing the ability of these models to truly predict in vivo CNS exposures of therapeutics, through an EU network of BBB translational scientists. The synergistic expertise of the partners in cellular and molecular biology, neuroscience, pharmacology, virology, drug delivery and bioinformatics along with the chemical/analytical resources, powerful biologics production facilities and direct link to the clinic brought by the EFPIA partners will enable rapid identification of new target mechanisms for brain delivery of therapeutics to treat neurodegenerative diseases and potentially wider applications in other CNS disorders.
