Abstract |
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.
|
Authors | L Bočkor, G Bortolussi, A Iaconcig, G Chiaruttini, C Tiribelli, M Giacca, F Benvenuti, L Zentilin, A F Muro |
Journal | Gene therapy
(Gene Ther)
Vol. 24
Issue 10
Pg. 649-660
(10 2017)
ISSN: 1476-5462 [Electronic] England |
PMID | 28805798
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- UGT1A1 enzyme
- Glucuronosyltransferase
- Bilirubin
|
Topics |
- Animals
- Bilirubin
(metabolism)
- Brain
(metabolism)
- Crigler-Najjar Syndrome
(therapy)
- Dependovirus
(genetics)
- Female
- Gene Transfer Techniques
- Genetic Therapy
(methods)
- Genetic Vectors
(genetics)
- Glucuronosyltransferase
(genetics, metabolism)
- HEK293 Cells
- Humans
- Liver
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Serogroup
|