Pasquale Piccolo, PhD - "Rethinking AAV-mediated gene therapy for fibrotic livers"

Pasquale Piccolo, PhD
Assistant Investigator
Tigem - Telethon Institute of Genetics and Medicine
Pozzuoli (NA)


Short CV

Abstract
Liver-directed gene therapy by adeno-associated viral (AAV) vectors has demonstrated transformative potential for several inherited disorders, yet the presence of liver fibrosis and chronic injury remains a major barrier to clinical translation. Fibrotic remodeling disrupts sinusoidal architecture, reduces permeability and, as we recently showed, promotes viral uptake by non-parenchymal cells and extra-hepatic organs, collectively impairing hepatocyte transduction and redirecting vector particles toward non-therapeutic compartments. In parallel, hepatocyte proliferation—triggered either by chronic injury or by the natural growth of pediatric livers—progressively dilutes episomal AAV genomes, limiting the durability of transgene expression. In addition, the development of fibrosis is associated with the creation of a pro-inflammatory microenvironment and with the recruitment and activation of immune cells, which display increased uptake of viral particles under conditions of hepatic fibrosis. These findings suggest that fibrosis and liver injury may represent an additional risk factor for immune-mediated adverse events.

Our research focuses on these critical challenges by integrating capsid prioritization and engineering, to improve vector performance in fibrotic livers, and genome editing to achieve durable correction even under conditions of hepatocyte turnover. In parallel, we are investigating how liver fibrosis shapes AAV immune profile, with the goal of identifying pathways that may be leveraged to improve safety and extend therapeutic efficacy. Together, these efforts aim to establish disease-informed approaches for safe and effective liver-directed gene therapy in inherited metabolic and cholestatic disorders.