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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - NEW DEAL (New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinases)

Teaser

Summary

The NEW DEAL project aims at developing new therapeutic strategy for inflammatory bowel diseases (IBDs), which are the most common immune disorders in young adults in Europe (affecting about 2.3-3 million people) with an increasing incidence. Conventional and biological therapies using anti-inflammatory drugs and/ or specific antibodies targeting TNFÎ± still leave a significant number of IBD patients insufficiently treated. The NEW DEAL therapeutic strategy relies on several innovations in the biomedical field: on one hand the therapeutic molecules will be specific siRNAs allowing a specific and sensitive inhibition of new molecular targets (targeted medicine) and on the other hand, these novel bio-therapeutics which are vulnerable to enzymatic degradation in biological environment will be delivered to the inflamed gut through smartly designed lipid nanoparticles, which enable their protection and their transport across biological barriers (nanomedicine). If successful, NEW DEAL will have a beneficial impact on the quality of life of many IBD patients and also will strongly decrease the costs linked to IBDs. In NEW DEAL, the new bio-therapeutics (siRNA targeting some kinases) as well as their delivery technologies will be properly designed and validated at the preclinical level by using the most relevant models of biological barriers and/ or experimental colitis. This will allow us to prepare the future clinical translation, by taking into account all regulatory requirements.

Work performed

We have designed siRNA sequences targeting human JAK1, human JAK3, murine JAK1 and murine JAK3 and validated their specificity in in vitro models. The selected sequences lead to a very high downregulation efficiency without observed neither off-target effects nor unwanted Toll-like receptors activation up to now. Investigations are still on-going to study the phenotypic outcomes on these silencing. In parallel, nanostructured lipid carriers have been designed and prepared in order to carry siRNA biomolecules. These particles presented very high colloidal stability and a good safety profile. We have validated that they were compatible with preparation processes of formulations for human administration (rectal and/or oral dosage forms), like spray drying. The models of mucus and intestinal epithelium have been set up and the ability of the particles and the siRNAs to cross these biological barriers under inflammatory conditions are still under investigation. In addition, first biodistribution studies in rodent models of experimental colitis indicated encouraging preliminary results with lipid particles being detected in some cell subpopulations from the inflamed gut. Stability of nanocomplexes (siRNA loaded lipid nanoparticles) is under evaluation and optimization. Initial draft of the clinical development plan has been drawn and the main regulatory requirements have been identified and shared with the consortium.

Final results

siRNA therapeutics have been poorly investigated in a context of inflammatory bowel diseases. They bring new possibilities for targeted medicines with a good control on their immunogenicity and bioavailability when delivered with appropriate carriers, as compared to therapeutic antibodies. This is of a great interest, especially since relevant molecular targets in IBDs have been recently identified in clinics with promising outcomes by using chemical inhibitors. However, the lack of specificity and their systemic effects hamper the clinical approval of these approaches. siRNA therapeutics have the potential to overcome these limitations. Local delivery can be achieved through the use of smart carriers. Up to now, none carrier has been approved in clinics to deliver biomolecules across the intestinal barrier. If successful, NEW DEAL will design and validate at the late preclinical level such a carrier. The nanostructured lipid carriers we develop in NEW DEAL present numerous advantages in a perspective of future clinical translation and industrial transfer, in terms of manufacturing processes, stability and safety. Both the siRNA therapeutics and the lipid carriers could have significant economic impacts, even beyond an IBD context.