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New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinases

Periodic Reporting for period 3 - NEW DEAL (New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinases)

Reporting period: 2020-01-01 to 2021-09-30

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.

At the end of the period 3, we demonstrated an active delivery of siRNA in the immune cells after rectal administrations in mice and its knockdown activity in various in vitro models from human origin. The initial toxicological package as conducted showed no safety concerns. We addressed the large scale production of nanostructured lipid carriers and initiated the transfer toward a French CDMO. Moreover, we tested an oral dosage form of siRNA/ NLC complexes with encouraging results about their protection along the GI tract. Finally, an early market analysis study has been completed, as well as a solid draft of Clinical Development Plan (CDP) & Draft Briefing Document for Regulatory Agency Meetings.

The three main innovations of NEW DEAL are the following:
- the formulation of nanostructured lipid carriers for delivering siRNA. The collaboration between GTP Nano and CEA Leti addressing the process development and their transfer is still on going.
- siJAK1 delivered through NLC technology (2 patents FR1907968 July 2019 and FR1907965 July 2019): this innovation will be promoted by the CEA team in the near future in order to continue the road of development toward clinical testing. We will try to identify the appropriate European calls to move forward toward the next steps with the core consortium of NEW DEAL. Moreover, we will work at promoting the innovations at the industrial level through active plan of prospection of relevant companies.
- New in vitro models : two NEW DEAL partners (HZI and Prodigest) have developed new models, a leaky model of inflamed gut based on the triple culture model (HZI) and the miniaturised SHIME model respectively (Prodigest, 1 patent EP 3 635 088 A1). These new models are now implemented in the respective organizations and used for their scientific and/ or commercial activities, strengthening their positioning and/ or offers.
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.

With the NEW DEAL project, we demonstrated an efficient delivery of siRNA into the immune cells of the inflamed gut by using lipid nanoparticles. Moreover, the JAK1 target has been confirmed by recent clinical investigations, with safety concerns recently raised by regulatory agencies. This confirms that a targeted approach is still highly anticipated for IBD patients, relying on the inhibition of JAK1 signaling cascade. NEW DEAL objectives still fits perfectly with these unmet clinical needs. Moreover, we have also evidenced the relevance of using new models and a panel of models to study the activity of biotherapeutics, including human organoids.
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