GENEGUT · Oral delivery of encapsulated RNA nanotherapeutics for targeted treatment of ileal Crohn's disease

Crohn’s disease is a non-communicable, global disease with an accelerating incidence (up to 23 per 100,000 persons/year) and annual health costs in excess of 5 billion euro in Europe. Despite advances in new immune modulators and biological treatment, up to 30% of patients become non-responders, highlighting the pressing need for novel, advanced therapies. GENEGUT will transform treatment of ileal Crohn’s disease (CD) by developing a first-in-class oral RNA-based therapy, tackling inflammation locally in the intestinal tissue, while avoiding systemic side effects. The success of mRNA covid vaccines demonstrated the potential of RNA-based therapies; the challenge is to extend this revolutionary therapeutic modality to non-communicable diseases where RNA delivery has not been achieved, such as ileal CD. Delivery of RNA will be enabled by a combination approach where novel biomaterials, including amphiphilic cyclodextrins and amino polyesters (both patented by partners), designed to overcome the barriers in the gastrointestinal tract will complex the RNA within nanoparticles (NPs). Our industry partner’s novel capsule technology will ensure site-specific release of the encapsulated NPs at the diseased ileum. The RNA-nanotherapeutics (siRNA and mRNA) will modulate gene expression locally in the ileum by targeting the clinically validated (JAK/STAT) pathway and two exploratory targets, Gremlin and Adrenomedullin. Proof-of-efficacy will be demonstrated in vivo and also in a 3D multi-cellular model of ileal CD using primary human cells. GENEGUT brings together 9 partners from 8 European countries covering the lifecycle from bench to bedside, creating a network of renowned researchers, expert clinical scientists, SMEs and larger pharma companies and a patient organisation. GENEGUT will result in an oral RNA therapeutic ready for early clinical trial including coherent plans for clinical trials and regulatory submission thus enabling rapid availability for patients.