학술논문

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
Document Type
Academic Journal
Source
Gene Therapy. October 2017, Vol. 24 Issue 10, 649
Subject
Gene therapy -- Usage
Crigler-Najjar syndrome -- Diagnosis -- Care and treatment
Immune response -- Research
Bilirubin -- Research
Health
Diagnosis
Care and treatment
Usage
Research
Language
English
ISSN
0969-7128
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[sup.-/-] 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. Gene Therapy (2017) 24, 649-660; doi: 10.1038/gt.2017.75; published online 7 September 2017
Author(s): L Bo[c caron]kor [1]; G Bortolussi [1]; A Iaconcig [1]; G Chiaruttini [1]; C Tiribelli [2]; M Giacca [1]; F Benvenuti [1]; L Zentilin [1]; A F Muro [1] [...]