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What did the project achieve?
“We’ve made important progress towards bringing this new treatment closer to a clinical trial for children with a severe inherited liver disease,” says Professor Paul Gissen of UCL Great Ormond Street Institute of Child Health. “Our goal is to develop an effective, less invasive alternative to liver transplantation – sparing children from the long waits and complications often associated with that procedure.”
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by faults in a gene called ABCB4, which provides the instructions for making a protein essential for healthy liver function. In children with PFIC3, bile – the digestive fluid produced by the liver – lacks a substance that protects the cells lining the bile ducts from its corrosive properties, causing progressive damage that can eventually lead to liver failure. Currently, the only curative treatment is a liver transplant – a major operation with significant risks and it is limited by a shortage of donor organs.
This research set out to develop a new gene therapy for PFIC3 using a harmless virus to deliver a healthy copy of the ABCB4 gene to liver cells, targeting the root cause of the condition.
“For the first time, we have successfully manufactured the treatment in sufficient quantities and the quality standard that will be required for future clinical trials,” says Professor Gissen. “We then tested the therapy in cells grown in the laboratory and confirmed that the treated cells produce the ABCB4 protein correctly.”
While similar gene therapies have been used safely to treat other inherited conditions, many previous approaches have required cells to be removed from the body, treated, and then transplanted back into patients.
“Our method delivers the treatment directly into the bloodstream so it can reach the liver – an important and innovative advance,” says Professor Gissen. “The results are very encouraging – a single dose restored ABCB4 protein function and improved liver symptoms in a laboratory model of the disease, with no safety concerns identified to date.”
Based on these findings, the team is now seeking external funding to advance this gene therapy into a clinical trial for people with PFIC3.
This research was completed on
How are children’s lives affected now?
PFIC3 is caused by faults in a gene called ABCB4, which provides the instructions to make a protein needed for healthy liver function.
“A child with PFIC3 will experience severe itching, yellowing of the skin and whites of the eyes – and slower than expected growth,” says Professor Gissen. “These symptoms will usually start in the first year of life and get worse over time, leading to complete liver failure later in childhood or early adulthood.”
In children with PFIC3, the bile – a digestive fluid produced by the liver – lacks an essential component that protects the cells lining the bile ducts (the tubes along which the bile flows from the liver) from the corrosive properties of bile. Eventually, these damaged cells stop working and the liver fails.
“A liver transplant is the only curative treatment for PFIC3 – but this is a major operation and the need for new livers far outweighs the number of donors,” says Professor Gissen. “There is an urgent need for alternative treatment options for children with this serious condition.”
How could this research help?
Our long-term goal is to develop a new gene therapy for children with liver disease caused by faults in the ABCB4 gene.
The researchers plan to use a harmless virus to deliver a working copy of the ABCB4 gene into liver cells. This type of gene therapy has successfully been used to treat other genetic diseases and shown to be safe.
“We will test our new gene therapy in the laboratory to find out if it is a safe and effective way of treating liver disease,” says Professor Gissen.
If this treatment shows promise, it could be a stepping stone toward setting up a clinical trial for children with PFIC3.
“If successful, this innovative gene therapy could help to transform the lives of children with PFIC3 – sparing them from the long waits and complications often associated with liver transplants,” says Professor Gissen.
It could also pave the way to the development of similar gene therapies for children with other severe liver diseases in the future
Research table
Project details
| Project Leader | Professor Paul Gissen MD PhD FRCPCH |
| Location | Department of Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London |
| Project Team |
Professor Paul Gissen, MD PhD FRCPCH
Mr Claudiu Cozmescu, BSc MSc Professor Simon N Waddington, BSc MSc PhD Dr John Counsell, BSc PhD Dr Julien Baruteau, MD PhD FRCPCH Dr Giandomenico Turchiano, BS MS PhD |
| Other Locations |
UCL Elizabeth Garrett Anderson Institute for Women’s Health, University College London
Division of Surgery and Interventional Science, University College London Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health |
| Grant Awarded | |
| Grant Amount | £183,934 |
| Start Date | |
| End Date | |
| Duration | 24 months |
| Grant Code (GN number) | GN2983 |
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