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New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinases

Periodic Reporting for period 2 - NEW DEAL (New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinases)

Reporting period: 2018-07-01 to 2019-12-31

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 TNFα 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.
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. The phenotypic outcomes of the JAK1 knockdown have been properly investigated in human cells, as compared to chemical inhibitors. Up to now, we do not observe significant impact on proliferation or cell death rates after JAK1 downregulation by the mean of siJAK1. . In parallel, nanostructured lipid carriers (NLCs) 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.We have demonstrated that the NLCs can diffuse across the mucosal barrier and can even reach the immune cells from the lamina propria after rectal administration in animal models.. We encountered some instability issue of the nanocomplexes (siRNA loaded NLCs) in colonic media, that we could overcome during the period 2, by promoting the interaction of siRNA to the particles through its chemical modification.. Draft of the clinical development plan has been drawn and the main regulatory requirements have been identified and shared with the consortium, but these tasks have been hampered by the technical issue of nanocomplexe instability, which has delayed the preclinical validation.All our efforts are done to achieve the solid proof of concept at the preclinical level for the last period, which is needed to fulfil the clinical development plan.
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. Moreover, the recent approval of patisiran the first siRNA therapeutics pave the way for future siRNA therapeutics. 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. Furthermore, none lipid carriers have been described at the preclinical level as able to deliver siRNA in the inflamed gut. If successful, NEW DEAL will design and validate at the late preclinical level such a carrier. The results will be far beyond the current state of the art in the field. 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.
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