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NEW DEAL

The aim of the NEW DEAL initiative is to design the next generation of biological therapy
for inflammatory bowel diseases.
Publié le 6 janvier 2021



NEW DEAL : New siRNA Nanotherapy for Inflammatory Bowel Diseases, targeting Janus kinase 1 and 3

​The aim of the NEW DEAL initiative is to design the next generation of biological therapy for inflammatory bowel diseases. These immune disorders of the gut, including Crohn’s disease and ulcerative colitis, are chronic with an early onset in life, typically in adolescents and in young adults. These diseases decrease quality of life and can lead to life threatening complications (bowel perforation, cancer...).


 

Starting date : Jan 2017 > Jan 2021    Lifetime:48 months


Program in support : 


 

Status project : complete


CEA-Leti's contact 

                                               

 

Project Coordinator: CEA-Leti


Partners:  

  • Eurofins SEPS pharma, Prodigest (BE)

  • ERS, HIPS (DE)

  • Institut d’Investigacions Biomèdiques August Pi i Sunyer, NIT, Science seed (ES)

  • Inserm, Mayoli Spindler (FR)

  • Boyd Consulting (GB)




Target market: n/a


Investment:  € 6 m.

EC Contribution€ 6 m.

Stakes

  • The efficiency of currently available drugs, including steroids and immunosuppresses, as well as antibody-based therapies (anti-TNF approach) remains suboptimal for a large proportion of patients. The need of novel therapies persists in this context. Our concept is to develop a new targeted therapy for the inflamed gut based on using siRNA (the next generation of biological drugs after antibodies) to target and inhibit expression of proteins involved in inflammation cascades (janus kinases) and on a delivery system capable of supplying these nucleic acids to the immune cells at the colon level.

  • CEA-BIG has designed siRNA sequences targeting human JAK1, human JAK3, murine JAK1 and murine JAK3 and has validated their specific characteristics based on in vitro models. The selected sequences lead to a very high regulation efficiency without observing off-target effects or unwanted Toll-like receptor activation to date. Investigations are ongoing to study the phenotypic outcomes on silencing. In parallel, CEA-Leti has designed and prepared nanostructured lipid carriers to transport siRNA biomolecules. 
    exhibited very high colloidal stability and a good safety profile. We have validated their compatibility with formulation preparation processes for human administration (rectal and/or oral dosage forms) such as spray drying or spray coating on solid carriers.

  • Models of mucus and intestinal epithelium have been built. The capacity of particles and siRNAs to cross these biological barriers under inflammatory conditions is still under investigation. In addition, first biodistribution studies in rodent models of experimental colitis have given encouraging preliminary results with lipid particles being detected in some cell subpopulations from the inflamed gut. The stability of nanocomplexes (siRNA loaded lipid nanoparticles) in very complexe colonic media is still under evaluation and optimization, yet major achievments were already completed. A first draft of the clinical development plan has been prepared and the main regulatory requirements have been identified and shared with the consortium.

OBJECTIVES


  • The NEW DEAL project aims to develop a new therapeutic strategy for inflammatory bowel diseases (IBDs), 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 TNF still leave a significant number of IBD patients insufficiently treated. The NEW DEAL therapeutic strategy relies on several innovations in the biome.

  • field. Therapeutic molecules will be specific siRNAs allowing a specific, sensitive inhibition of new molecular targets (targeted medicine) and thesenovel bio-therapeutics vulnerable to enzymatic degradation in biological environment will be delivered to the inflamed gut through smartly designed lipid nanoparticles offering protection and transport across biological barriers (barriers).

  • nanomedicine). If successful, NEW DEAL will have a beneficial impact on the quality of life of many IBD patients and will markedly reduce the IBD-related costs. In NEW DEAL, the new bio-therapeutics (siRNA
    targeting some kinases) and their delivery technologies will be designed and validated at preclinical level using the most relevant models of biological barriers and/or experimental colitis. This will allow us to prepare future clinical translation by taking into account all the regulatory


IMPACT

  • Deal siRNA therapeutics have been insufficiently investigated in the context of inflammatory bowel diseases. Compared with therapeutic antibodies, they offer new possibilities for targeted medicines with good control of immunogenicityand bioavailability, when delivered by appropriate carriers. This is of a great interest, especially since relevant molecular targets in IBDs have been recently identified in clinics along with promising outcomes using chemical inhibitors. However, the lack of specific characteristics 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. So far, no carrier has been clinically approved for delivering biomolecules across the intestinal barrier. If successful, the NEW DEAL project team will design and validate such a carrier at the late preclinical stage. The nanostructured lipid carriers developed in NEW DEAL offer multiple advantages with the prospect of future clinical translation and industrial transfer in terms of manufacturing processes, stability and safety. siRNA therapeutics and lipidcarriers could have significant economic impacts even beyond the IBD