Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model
Keywords: 
Materias Investigacion::Ciencias de la Salud::Genética
Issue Date: 
2019
Publisher: 
Springer Science and Business Media LLC
ISSN: 
2041-1723
Note: 
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
Citation: 
Weber, N.D. (Nicholas D.); Odriozola, L. (Leticia); Martínez-García, J. (Javier); et al. "Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model". Nature Communications. 10 (5694), 2019, 1 - 13
Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4-/- mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.

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