Liver disease is the fastest-rising cause of death in the UK, and for patients with bile duct failure, a transplant is the only option—but donor organs are scarce. This researcher has already built lab-grown bile ducts and bile duct cells, repaired damaged ducts in mice and in human livers kept alive outside the body, and scaled the technology to human size. Now she is pushing toward the first clinical trials. The core problem is that bile ducts, which drain toxic bile from the liver, can break down from acute injury or chronic disease. In acute cases, her cell therapy works. In chronic disease, the toxic environment kills transplanted cells and reprograms them to lose their healing ability. She discovered that the drug rapamycin can calm that hostile environment, and that epigenetic CRISPR editing can prevent the cells from losing their repair capacity. If this succeeds, it would offer the first alternative to liver transplantation for biliary disease. It could also allow surgeons to repair donor livers with damaged ducts, increasing the supply of transplantable organs. The techniques—combining cell therapy with drugs and epigenetic editing—could extend to other organs and set a regulatory template for future cell therapies in the UK.
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Challenge Liver disease is the most rapidly increasing cause of death in the UK. Transplantation remains the only treatment for end-stage disease, but it is limited by organ supply. This challenge becomes more pronounced for diseases with no other treatment options, such as disorders of the bile ducts in the liver. The bile ducts form a network of tubes that transfer toxic bile. When they break down, bile damages the surrounding tissue, causing liver failure. Biliary diseases are the leading cause for liver transplantation in children, a major indication for transplantation in adults and a cause of liver failure in ~30% of transplanted livers. Context I have been working on addressing this challenge since 2017. I generated lab-grown (bioengineered) bile ducts and bile duct cells and used them to repair damaged ducts in mouse models and in human livers (cell therapy). These livers were not used for transplantation but kept alive outside the body using a method called machine perfusion, which uses pumps to maintain blood through the organs. During the first part of my fellowship, I collaborated with industry (Bilitech LTD) and the UK Cell and Gene Therapy Catapult (CGTC), ensured that the cells met safety and quality standards for transplantation in humans, and upscaled my lab-grown ducts to human size. I tested the efficacy of lab-grown, human-sized duct prototypes with pilot pig experiments and completed successful preclinical testing of cell therapy for acute bile duct diseases (where injury stops after the damage has occurred). This technology is now ripe for clinical translation. In parallel, I tested cell therapy in animal models of chronic disease, where injury persists even after the ducts are destroyed. Transplanted cells could not survive in this toxic environment, but I discovered that using a drug called rapamycin could moderate injury and make the tissue more receptive to cell therapy. Furthermore, I discovered that the hostile environment changes the cells so that they lose their healing capacity (reprogramming), but this can be prevented using a cutting-edge technique called epigenetic CRISPR editing. My renewal proposal is the natural continuation of this work. Aims Advance lab-grown ducts and cell therapy for acute bile duct diseases to first-in-human studies. Optimise the efficacy of cell therapy for chronic disease, using the knowledge from the first part of my fellowship. Objectives Pursue regulatory approval for first-in-human studies for acute biliary diseases, supported by Bilitech and CGTC. Develop drugs enhancing cell therapy, in chronic biliary diseases. I will start with testing the efficacy of rapamycin in mice and machine-perfused human livers. Prevent cell changes after transplantation, with epigenetic CRISPR editing to prevent loss of their healing capacity. I will test these cells in mice and machine-perfused human livers. Potential applications and benefits This work will provide the first alternative to liver transplantation for patients with biliary disease. Repairing liver grafts with damaged ducts with cell therapy will increase organ supply and shift the paradigm for transplantation medicine. The transferrable technology generated will be applicable to multiple organs/cell types and advance the field to next-generation cell therapies with epigenetically-modified cells and treatment-enhancing drugs. Pursuing approval for first-in-human studies will map the regulatory landscape and set a point-of-reference for future cell therapies. Industry involvement will reinforce the UK’s leading position in cell therapy manufacturing, and promote economic growth.
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