Periodic Reporting for period 5 - IM2PACT (Investigating Mechanisms and Models Predictive of Accessibility of Therapeutics (IM2PACT) Into The Brain)
Período documentado: 2023-01-01 hasta 2023-12-31
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.
1. A comprehensive single cell atlas of the Alzheimer’s Disease brain.
We developed a novel and superior protocol for isolation of human brain neurovascular cells to allow us to produce a dataset of gene changes in individual cells in Alzheimer’s Disease. The dataset has been made available as an open research dataset (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE222007). The first manuscript using this data has been published (https://www.nature.com/articles/s41467-024-46630-z)
2. Understanding how obesity and high blood glucose affects the brain
We have investigated how obesity and high blood glucose affect brain neurovascular cell gene expression and the functioning of blood vessels in the brain. Our analysis highlights changes that overlap with Alzheimer's Disease processes suggesting the importance of preventing obesity and diabetes to reduce the risk of Alzheimer's Disease. A manuscript is being prepared for peer review and publication.
3. Human stem cell models to investigate the blood-brain-barrier.
A robust protocol has been established for the generation of brain endothelial-like cells from human induced pluripotent stem cells - the model exhibiting a tight barrier function and expression of molecules involved in transport across the barrier. This work has been published (https://doi.org/10.1186/s12987-023-00501-9). Additionally genome engineered stem cell lines where it is possible to knock-out expression of our selected target genes has been generated and will be a valuable tool for the community.
4. Implementation of a 3D-Model of the Blood-Brain-Barrier
To improve the ability to model the blood-brain-barrier, our consortium has established a 3D-spheroid model. This model better recapitulates some of the features of the blood-brain-barrier and will allow for investigation of disease drug targets.
5. Neurotropic Viral interactome
Neurotropic viruses have evolved to access the brain across the blood-brain-barrier. We have identified the proteins in brain endothelial cells that these viruses interact with. This work has highlighted that these types of viruses may bind to multiple proteins rather than a single specific receptor for brain entry. This will help guide future research to develop different strategies for passage across the blood-brain-barrier.
6. Prioritisation of SLC7A1 as a transport target and Alzheimer's Disease target
The molecular analysis highlighted this transporter as a good candidate to enable brain therapeutic access. A manuscript describing the identification is currently under review. To test the ability of SLC7A1 to transport therapies into the brain, specific antibodies against SLC7A1 are being developed. The analysis has also highlighted this transporter as having a role in disease and human stem cell models to investigate this further are being developed.