Periodic Reporting for period 2 - GENEGUT (Oral delivery of encapsulated RNA nanotherapeutics for targeted treatment of ileal Crohn's disease)
Período documentado: 2024-04-01 hasta 2025-09-30
The GENEGUT project aims to develop an oral medicine for the treatment of Crohn’s disease specifically located in the lower part of the small intestine called the ileum. Crohn’s disease is a form of IBD and is difficult to treat with medications currently available. It is a very debilitating disease, causing severe pain and intestinal upsets, it has negative effects on quality of life, patients frequently loose days at work and often have to undergo surgery. For these reasons new improved medicines are required and GENEGUT aims to meet this need. The drug incorporated in the GENEGUT medicinal product is RNA (ribonucleic acid) tailored made to tackle the root causes of the disease. While RNA has been shown to be effective, the big challenge is to ensure that it is protected from breakdown in the gut and that it arrives intact at the disease site, in this case at the gut wall of the ileum in the small intestine.
In order to protect the RNA, GENEGUT has produced two types of packaging materials called cyclodextrins and amino polymers. These materials enclose the RNA in tiny particles called nanoparticles (NPs) thus protecting the RNA from attack by damaging enzymes. Once the NPs were made, they were tested in models of the intestine, built in the laboratory using human intestinal cells. The cell models were designed to reflect both healthy and diseased states and were used to test the ability of the NPs to decrease the disease symptoms. GENEGUT has now identified the best performing NPs and these are undergoing further evaluation in a more complex models including a 3D cell model which incorporates all the different cell types found in the live human intestine.
As the intestinal environment is very hostile to RNA the synthesis of effect protective packaging materials, as mentioned above, is a major achievement for GENEGUT. To administer the RNA NPs by mouth (orally) they must be dried and packed into capsules. The conditions used in the drying process have been optimised by GENEGUT to ensure the RNA remains active. GENEGUT has designed and made a novel capsule shell which can travel through the stomach intact and down the intestine to the lower ileum where it then releases the RNA cargo at the disease location. This capsule will ultimately be evaluated in a pig model of the disease. The establishment, by GENEGUT, of complex multicellular intestinal models capable of evaluating the therapeutic efficacy and the mechanism of action of the RNA NPs will contribute significantly to the state of the art and can be applied in future projects to evaluate the efficacy of other IBD therapeutics. These complex models can be used to predict the performance in humans, thus helping to reduce the need for animal experiments.