The BBB and Neuroinflammation team lead by M. Khrestchatisky was created in 2008 to expand the laboratory’s potential to study CNS diseases and neuroinflammation processes at the neurovascular level. Indeed, the CNS is endowed with a unique microenvironment that relies upon the integrity of the BBB. Most CNS diseases are associated with BBB inflammation, which plays an integral role in the inflammatory response by expressing a variety of cytokines, adhesion molecules, products of arachidonic acid metabolism, nitric oxide serine and metallo-proteinases, etc. Understanding the role of the BBB during inflammation in general, and specifically in the course of different diseases is paramount for the develoment of therapeutic strategies aimed at controling the deleterious effects of inflammation. We thus developed projects addressing pro-inflammatory molecular systems such as the MMP/TIMP system and the TWEAK cytokine or the anti-inflammatory molecule pantethine (B. Gharib/M. De Reggi) in different pathological situations such as spinal cord lesions and repair (collaboration with F. Féron), multiple sclerosis (S. Desplat-Jego) and Alzheimer’s Disease (collaboration with S. Rivera) and glioblastoma (ongoing ANR project). Another focus of the team was to exploit the knowledge and technology generated in the lab on the BBB, notably in the context of inflammation, to address CNS drug delivery across the BBB. This objective is pursued in close interaction with VECT-HORUS, a biotechnology company spin off from our Team, created for translational research and transfer with whom we develop vector molecules that facilitate drug transport across the BBB and novel therapeutic drugs based on the conjugation of our vectors with off patent or proprietary drugs and imaging agents.
The general objective of the Team is to pursue with the INP experts ongoing collaborations on neuroinflammation, the MMP/TIMP system, AD models and APP processing (S. Rivera team), neural stem cells and iPS technology (F. Féron and E. Nivet teams), gliomas, tumour processes (D. Figarella-Branger/D. Braguer, L’H. Ouafik, H. Kovacic/V. Peyrot teams), nanoparticle design and development (D. Braguer), CNS imaging (C. Leterrier team). The team will pursue its research and development at different levels of integration, ranging from chemistry and drug design, molecular and cellular neurobiology, to the most integrated studies with animal models of pathology, behavior, learning and memory (F. Roman team), and preclinical studies. Transfer and valorization for the team’s research will be optimized by the original structure of the INP (Laboratoire Commun de Recherche, LCR), which integrates the academic teams mentioned above, the VECT-HORUS company and its industrial partners.
1. BBB inflammation and demise in CNS diseases
PIs: P. Benech, L. Ferhat, M. Khrestchatisky; collaborations with S. Desplat Jego, S. Rivera, E. Nivet, partnership with VECT-HORUS.
We will pursue our studies on the transcriptome/proteome of diseased brain microvessels prepared from animal models of different pathlogies, at different stages of the pathology and CNS endothelial cells in culture (in vitro BBB systems), stimulated or not with different pro- or anti-inflammatory molecules. Molecules of interest and critical pathways will be identified using systems biology approaches. With VECT-HORUS, we will also pursue the ongoing development of human in vitro BBB models based on iPS stem cell technology that will allow implementation of in vitro BBB models based on human cells. These cells will be derived from patients, and we anticipate co-culture models of the neuro-glia-vascular unit (collaboration E. Nivet and S. Rivera). Results obtained in vitro will be confronted with in vivo data obtained from brain microvessels of animal models and from human.
2. Identification of new BBB receptor targets and development of optimized vector molecules
PIs: M. Khrestchatisky, L. Ferhat, P. Benech partnership with VECT-HORUS
Receptor-mediated transcytosis/transport (RMT) is considred as the safest and most efficient strategy to transport drugs or imaging agents into the brain. Different laboratoires and biotech companies have focused on a “first generation” family of receptors, expressed at the BBB, but also in organs of the periphery, draining vectorised molecules and potentially eliciting secondary or toxic effects. There is thus a need to identify “second generation” receptors that are expressed at high levels at the inflamed BBB and as BBB-specific as possible. In collaboration with VECT-HORUS we will pursue our studies on the transcriptome/proteome of CNS endothelial cells from animal models of different pathologies and from human in vitro BBB models based on iPS technology. Brain endothelial cell receptors identified as targets of interest will be validated. In parallel, we will also implement high throughput screening of stable cell lines expressing receptors of interest and purified receptor domains with linear and cyclic peptide libraries and with nanobody libraries (collaboration D. Baty, CRCM, NANOVECTOR ANR project). Finally, we will develop and optimize peptide or nanobody hits as bona fide vectors and evaluate their potential to transport different types of drugs (small organic, siRNA, bio-molecules such as a peptides, antibodies, enzymes etc.).
3. The development of novel vectorised drugs and imaging agents
PI: M. Khrestchatisky, partnership with VECT-HORUS
Once validated, (efficient, BBB-specific, non toxic) novel vectors will be conjugated to imaging agents or different drugs of interest, either off-patent organic drugs or bio-molecules (siRNAs, endogenous peptides, antibodies, enzymes) or proprietary molecules of the biotech or pharma industry. Conjugates will be assessed for their potential to cross the BBB and reach the nervous tissue to elicit efficacy. They will be further developed as new chemical entities to be developed up to preclinical studies before licensing to pharma or biotech partners.