Hepatocyte-directed gene therapy for inherited disorders with liver fibrosis
Our research focuses on gene-based therapies for inborn errors of metabolism that cause liver injury, progressive fibrosis, and cirrhosis. This includes conditions such as Wilson disease (WD), progressive familial intrahepatic cholestasis (PFICs), and α1-antitrypsin deficiency (AATD). These disorders are marked by chronic damage to liver cells, accumulation of extracellular matrix, scarring, and significant changes in both the liver and the overall immune environment. All these factors can greatly affect how well in vivo gene therapy and genome editing perform, as well as how long-lasting and safe their effects are.
A key aspect of our work is to understand how fibrotic liver tissue interacts with adeno-associated viral (AAV) vectors. We recently examined how fibrosis alters AAV tropism, distribution, and cell targeting. We also investigated how changes in the liver's microenvironment due to disease affect gene transfer efficiency based on the capsid used (Ferriero et al., Nat Comm 2025). These findings provide a basis for designing engineered AAV capsids that are optimized for effective and selective delivery to liver cells in fibrotic livers. Our goal is to improve gene delivery in patients with severe liver damage.
At the same time, we are developing genome-editing strategies for WD and PFIC3 to tackle a major limitation of traditional AAV-mediated gene transfer in children and those with chronic liver disease. This limitation is the gradual dilution of episomal vectors due to hepatocyte proliferation and liver growth. By combining liver models relevant to the disease with targeted integration and lasting genome correction strategies, we aim to achieve long-term therapeutic benefits in situations where ongoing cell turnover would normally reduce the impact of gene therapy.
Liver fibrosis itself is a significant unresolved issue in chronic liver disease. It is common across both genetic and acquired causes and there are currently no effective anti-fibrotic therapies. We have identified the microRNA miR-34b/c as a regulator of pathways that lead to fibrosis in the liver (Piccolo et al., PNAS 2021). We are advancing miR-34b/c-based strategies as a treatment for both inherited and acquired liver fibrosis (Piccolo et al., Mol Ther Nucl Ac 2025).
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Understanding and treating rare genetic diseases is a wonderful journey and an extraordinary creative adventure that teaches us a lot about human life and health.
Additional Funding
- EC- AAVolution - Next-generation AAV vectors for liver-directed gene therapy (2022-2026)
- ALP, ALPHA1-FOUNDATION “Development of RNA Aptamers Inhibiting Polymerization of Mutated Z Alpha-1-Antitrypsin.” (2025-2027)
- PFIC Network - “HITI-based promoter-less genome editing for the treatment of PFIC3” (2024-2026)