Discovery and characterisation of blood-brain barrier targets and transport mechanisms for brain delivery of therapeutics to treat neurodegenerative & metabolic diseases

The objectives of the project to be delivered from this topic are:

1. establishment and characterisation of BBB models relevant for healthy and disease conditions for evaluation of disease-modifying agents (human in vitro cell based, in particular iPSC or progenitor-derived cells, and in vivo);
2. identification of translational readouts closer to the pathogenesis of neurodegeneration and mimicking altered BBB under disease conditions;
3. in-depth understanding of the biology of the BBB and characterisation of various transport mechanisms across the BBB (including virus-mediated BBB and Central Nervous System(CNS) penetration);
4. discovery and development of innovative and efficacious brain delivery systems.

These objectives could be attained through the milestones shown hereunder. Each of them could represent an independent work package and will be described later in the topic text:

1. select specific genes and pathways expressed in endothelial cells of normal and/or diseased human brains or preclinical models;
2. validate in vitro and in vivo that these genes or pathways are responsible for normal/deficient/altered transport at the BBB and the impacts of disease development and progression on these genes or pathways;
3. this will enable the generation of improved BBB models for neurodegenerative/metabolic diseases predictive for the disease situation with optimized in vitro-in vivo correlation compared to established models; develop in silico models for predicting BBB penetration and pharmacokinetics of therapeutics in CNS;
4. identify and validate novel targets for brain delivery;
5. understand the mechanisms of neurotropic virus-mediated BBB and CNS penetration to inform innovative ways of brain-selective delivery.

Several challenges have yet to be addressed to better understand the role and alterations of the Blood Brain Barrier (BBB) and transport mechanisms in health and diseases. This is particularly critical for neurodegenerative diseases (e.g. Alzheimer and Parkinson’s diseases, Amyotrophic Lateral Sclerosis (ALS)), vascular dementia, multiple sclerosis and metabolism-related central diseases (diabetes and obesity). It will be also important to understand the mechanisms of neurotropic virus-mediated BBB and brain penetration, and to be able to apply this knowledge for the development of innovative drug delivery systems, especially for biopharmaceuticals, and the identification of novel drug targets. Furthermore the various transport mechanisms and potential drug delivery systems that have been suggested so far need validation by independent researchers and the further understanding of challenges to advancing into clinical drug development by biotech/pharma.

The use of ‘healthy’ and patient-derived specimens, inducible pluripotent stem cell (iPSC) clones and other types of progenitors offers compelling approaches due to the direct connection to patients with the underlying disease. The impacts of these new models could include: (1) yielding novel insights into currently identified BBB transport mechanisms for drugs, especially biopharmaceuticals, (2) allowing to use comparative assessment between ‘healthy’ and ‘diseased’ BBB, including in silico models, to prioritise some approaches for specific disease(s) because the transport mechanism is modified in the disease state, (3) leading to the identification and characterisation of novel transport mechanisms that are unaffected or upregulated in the disease or neurotropic virus-mediated, making them even more interesting, and (4) facilitating the discovery and characterisation of novel targets addressing the vascular aspect of neurological disorders like AD and thus open up novel routes for therapy.