Development and evaluation of microRNA-based nanoscale delivery systems for inflammatory bowel disorders: DEMONSTRATE Study

Ulcerative colitis (UC) and Crohn’s disease are chronic, relapsing inflammatory disorders of the gastrointestinal tract. These inflammatory bowel diseases (IBD) can result in debilitating physical and psychosocial symptoms for patients and affect society through loss of schooling, absenteeism, and healthcare costs. In 2019, there were approximately 4.9 million people living with IBD worldwide. Research commissioned by Crohn’s and Colitis UK and carried out at the University of Nottingham found that over 1 in 123 people are living with IBD in the UK in 2022. Lifetime costs for the NHS for treating IBD are comparable to heart disease and cancer. Patients with IBD are highly susceptible to bowel infections cause by harmful bacteria such as Clostridioides difficile. Disease-causing strains of C. difficile produce toxins which damage the gut barrier and can lead to severe inflammation of the bowel. Patients infected with C.difficile often experience more severe IBD flares with higher rates of hospitalisation, bowel damage requiring bowel resection, and death. However, management of C. difficile in IBD patients is exceptionally challenging. Moreover, the medical need for new treatments to control IBD durably and effectively remains very high. We have recently discovered that small molecules (miRNAs) found in the blood and intestine act as brakes on inflammation and are decreased in patients with recurrent C. difficile infection (CDI). These same miRNAs are also decreased in mouse models of colitis. We have shown that successful intestinal microbiota transplants or poo transplants from healthy donors to patients with C. difficile can replace these anti-inflammatory miRNAs. We found that that a specific combination of miRNAs which are carried by tiny synthetic particles called ‘nanoparticles’ can protect human intestinal cells from damage caused by microbial toxins and other inflammatory triggers. These nanoparticles act as smart carrier vehicles to deliver the therapeutic miRNAs to the desired location in the intestine by helping to protect the miRNAs from stomach acids. We believe that these miRNA-based nanoparticles may represent promising therapeutic drug candidates for both IBD and CDI by protecting the gut barrier and decreasing inflammation. miRNA-based treatments are beginning to show therapeutic promise, but currently there are no C. difficile-specific miRNA therapeutics and only one anti-inflammatory IBD microRNA-based treatment, Obefazimod, which has shown significant clinical efficacy in UC clinical trials. In this project, we aim to firstly create a panel of novel carrier nanoparticles with extremely small or ‘nanoscale’ dimensions to deliver the miRNAs to the intestinal cells. These nanoparticles which are undetectable by the human eye, will help facilitate the proficient and safe delivery of our therapeutic miRNAs to the intestine. In early screening assays, we will then evaluate the safety and ability of these to protect the gut barrier from inflammatory insults in a state-of-the-art human gut tissue models composed of intestinal and immune cell populations. miRNA treatments which show the greatest protective potential will be evaluated in clinically relevant human miniguts or ‘gut-on-a-chip’ and animal (mouse) models of IBD and CDI. Our project will also dissect the molecular mechanisms of action of these miRNA therapeutics using ground-breaking chemical analysis as well as molecular and microbial profiling methods. These analyses will help identify potential measures of effect of our miRNA-based treatments for therapeutic approval and potential ‘off-target’ or unwanted effects, which is an unmet need in RNA therapeutics development.