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[Gene therapy for acute hepatitis using CrmA gene transduction]
1Department of Genetics, National Children's Medical Research Center, Tokyo, Japan.
Human Cell
|March 1, 2000
Summary
Cytokine response modifier A (CrmA) prevents apoptosis in adenovirus-transduced hepatocytes, extending transgene expression. Co-expression of CrmA with therapeutic genes prolongs their functional lifespan in liver gene therapy.
Area of Science:
- Gene Therapy
- Immunology
- Hepatology
Background:
- Adenovirus-mediated gene transfer to hepatocytes is limited by Fas-mediated apoptosis induced by cytotoxic T lymphocytes (CTLs).
- Cytokine response modifier A (CrmA) inhibits caspase 8, protecting cells from Fas-induced apoptosis.
Purpose of the Study:
- To investigate the efficacy of an E1-deleted adenovirus expressing CrmA in preventing Fas-mediated apoptosis of hepatocytes.
- To assess the impact of CrmA co-expression on prolonging transgene expression in adenovirus-transduced hepatocytes in vivo.
Main Methods:
- Generation of an E1-deleted adenovirus encoding CrmA.
- In vitro assessment of CrmA's anti-apoptotic effect on hepatocytes using anti-Fas antibody.
- In vivo study in mice with lysosomal beta-glucuronidase (GUSB) deficiency, co-administering adenoviruses for GUSB and CrmA.
Main Results:
- Hepatocytes expressing CrmA demonstrated resistance to anti-Fas antibody-induced apoptosis.
- Co-administration of CrmA-expressing adenovirus with a GUSB-expressing adenovirus significantly prolonged GUSB activity in mouse serum and liver for over 130 days compared to GUSB alone (disappeared within 70 days).
Conclusions:
- Exogenous CrmA expression confers resistance to Fas-mediated apoptosis in hepatocytes.
- CrmA co-expression is a viable strategy to enhance the duration of transgene expression in liver gene therapy using adenoviral vectors.