10162701Reprogramming the Gut: AI-Optimised Nucleases for Targeted Gut RepairActiveFeasibility StudiesInnovate UKOur project focuses on developing synthetic biology tools "molecular scissors" to create innovative microbiome-targeting treatments for Inflammatory Bowel Disease (IBD). IBD is a long-term condition causing painful inflammation in the digestive system, and leading to symptoms like stomach pain, tiredness, rectal bleeding and diarrhea and can result in serious complications like surgery (e.g., bowel resection or colectomy) and an increased risk of colorectal cancer. In the UK, more than 500,000 people live with IBD, and the number is increasing, especially among young adults, putting more pressure on healthcare services. Current treatments can help manage symptoms but often have side effects and don't fix the underlying problem. Our solution focuses on the gut microbiome, the community of bacteria that lives in the digestive system. In people with IBD, this ecosystem becomes unbalanced, leading to inflammation and a weakened gut barrier. Our treatment for IBD focuses on: 1. Removing harmful bacteria using special proteins called nucleases, which act like precise molecular scissors. 2. Reprogramming helpful bacteria so they can produce anti-inflammatory compounds and support the formation of tight and adherens junctions in the gut, improving barrier integrity and reducing permeability to reduce inflammation and help repair the gut lining. Machine learning was used to design a set of synthetic nucleases (molecular scissors editing DNA). These are similar to CRISPR, but may be smaller and more targeted for our purposes. Using machine learning, 200 potential nucleases were designed and 20 most promising were selected through AI modelling for further testing. In this project, we will test and improve these 20 nucleases in the lab. We'll assess: 1. How well they work at editing target genes in selected bacteria. 2. How safe they are, making sure they don't cause unwanted changes elsewhere. By the end of the project, we aim to advance these nucleases from an early stage of development, TRL 2, to the proof of concept level, TRL 3\. This will prepare the groundwork for future patents, partnerships, and clinical trials, bringing us closer to a novel approach in microbiome-targeting treatment for people living with IBD.