Naslov
Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler–Najjar Syndrome Type I

Autori
Bočkor, Luka ; Bortolussi, Giulia ; Iaconcig, Alessandra ; Chiaruttini, Giulia ; Tiribelli, , Claudio ; Giacca Mauro ; Benvenuti, Federica Zentillin, Lorena ; Muro, Andrés F.

Izvornik
Gene therapy (0969-7128) 24 (2017); 649-660

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
AAV-mediated gene therapy, liver, Crigler-Najjar Type I, Ugt1a1, mouse models

Sažetak
Adeno-associated virus (AAV) -mediated gene therapy is a promising strategy to treat liver- based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector ; second, development of an immune response against the transgene and/or viral vector. Crigler–Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1−/− mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV- therapeutic efficacy by repeated administration.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Kliničke medicinske znanosti, Biotehnologija

POVEZANOST RADA