Inflammatory bowel diseases (IBD) comprises a group of chronic inflammations of the gastro-intestinal tract. The two main types are Crohn's Disease and Ulcerative Colitis. While IBD has been extensively studied in the past decades and especially recently since emerging technologies enabled DNA sequencing of intestinal bacteria, the development of new treatments have been progressing slowly. Only recently, some more specific therapies like antibodies that target leukocytes’ trafficking (e.g. against α4β7 integrin) or against pro-inflammatory cytokines (e.g. anti- TNF-α) are being used. Because of the complexity of intestinal immunity, we believe that a tailor-made therapy is required. We are working on a project that targets lipid nanoparticles (LNPs) specifically to immune cells actively participating in the intestinal inflammation. We do this by coating the LNPs with a protein that contains part of MAdCAM-1, the natural ligand of α4β7 integrin. This ligand recognizes only the high-affinity conformation of α4β7 integrin, a conformation that enables immune cells to migrate to the gut. Using this system, we show that we can deliver therapeutic siRNAs specifically to these cells while leaving other cells untouched.
The incidence of IBD in Europe is rising (> 1% of the EU suffer from IBD) and with it, its associated healthcare costs (~ 5 billion euro/year in 2013). Novel therapeutics like Humera and Entyvio are promising drugs but leave patients dependent on expensive monoclonal antibodies for a long period. We envision manipulating pro-inflammatory immune cells by silencing specific target genes and thereby we strive to restore the natural immunological balance.
As a result of this project, we also developed a strategy to immobilize mAb on the surface of lipid nanoparticles and control the orientation of the mAb on the LNPs’ surface. Using this approach we should systemic, cell specific delivery of siRNAs to leukocytes subsets (Kedmi R. et al. Nature Nanotechnology 2018; Dammes N. et al., Nature Nanotechnology 2021). In addition, we utilize this approach to show the first, systemic, cell specific delivery of mRNA into leukocytes (Viega et al. Nature Communications 2018; Veiga N. et al Journal of controlled release 2019) and the first systemic, therapeutic genome editing in cancer (Rosenblum D. et al Science Adv. 2020).
The main objective of this project is to deliver siRNA against a pro-inflammatory target (e.g. IFN-γ or TNF-α) in vivo in a colitis mouse model and achieve therapeutic efficacy. Furthermore, we are developing more accurate diagnostic and disease management tools by labeling the activated immune cells with Cu64 in out targeted LNPs to analyze the disease with PET/CT
