In vivo liver genome editing for the treatment of Alpha-1 antitrypsin deficiency


Professor Deborah Gill of John Radcliffe Hospital, University of Oxford discusses her research and what it means for the future of treating childhood liver disease. This research is co-funded by BSPGHAN and Children’s Liver Disease Foundation (CLDF).

What is this study looking at?

Gene therapy holds the promise of a curative treatment for genetic diseases by delivering a functional copy of a gene into cells to compensate for non-functional (defective) versions. This is called ‘gene addition’. However, the liver grows in paediatric patients, which means that the gene addition approach may only have a short-term impact.

This study is proposing a new strategy called genome editing to precisely insert a functional copy of the gene into the genome (complete set of genes or genetic material present in a cell or organism) of the patient’s liver cells, so that it could continue to function for the life-time of the patient.It will test the genome editing strategy on a mouse model of alpha-1 antitrypsin (A1AT) deficiency, in the hope it will replicate findings of tests with liver cells grown in culture and artificial ‘mini livers’ (organoids). The study hopes to evaluate the safety and therapeutic applicability before clinical trials can begin.

Why is this research important?

There is currently no definitive cure for AAT deficiency, however, genome editing provides an opportunity to address this unmet need. While this study focuses on AAT deficiency, it hopes to open the platform for exploration of other genetic liver diseases where genome editing may be beneficial.

There has been no previous paediatric study, to our knowledge, exploring the association of sarcopenia with increased fibrosis and/or inflammation in the context of NAFLD. No study in children with NAFLD has investigated the various myokines (products released by muscle cells) and adipokines (protein secreted by body fat) in relation to muscle mass.

What about the future?

If the strategy is successful in demonstrating genome editing of the A1AT gene in mice, the results will help progress this approach for clinical development. These results will also support further funding applications to use this approach for the treatment of other genetic liver diseases.

Return to current research projects