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发表于 2002-9-11 05:34
Vector Dampens Liver Cell
Resistance To Gene Therapy
NewsRx.com
July 18, 2002
by Sonia Nichols, senior medical writer
In most instances, immune response mechanisms are activated when foreign bodies such as viruses invade the human body. This has made the development of some gene therapies, especially those using viruses as delivery vehicles, particularly challenging.
Researchers at the University of Alabama in Birmingham may have found a way to overcome problems associated with using adenovirus-mediated delivery of gene therapies directed towards hepatocytes, or liver cells, by constructing a viral vector that neutralizes ligands and cytokines stimulated in response to hepatocyte infection.
According to H.G. Zhang and colleagues, both innate and cell-mediated immune system response play a factor in the death of hepatocytes following adenovirus-mediated treatment. Zhang and coauthors said that several cellular receptors such as those for tumor necrosis factor (TNF)-(alpha) and Fas, as well as those designated as death domain receptors (DR4 and DR5), facilitate apoptotic death and necrosis in liver cells after gene therapy, rendering them incapable of expressing therapeutic genes.
Building upon an earlier study that found blocking signals for the TNF-(alpha) receptor (TNFR) caused adenovirus-based gene therapy to be more effective, Zhang's group has developed an adenoviral vector encoding for soluble DR5-Fc that throws TNF-related apoptosis-inducing ligand (TRAIL) off balance.
"AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ (Adenovirus, cytomegalovirus, E. coli lacZ gene) administration and enhances the level and duration of lacZ transgene expression in the liver," described Zhang and coauthors.
The novel vector not only blocked apoptosis but also limited the production of several key immune response system cytokines known to affect genetic expression after vector delivery in the liver (Hepatic DR5 induces apoptosis and limits adenovirus gene therapy product expression in the liver, Journal of Virology, 2002;76(11):5692-5700).
Zhang and colleagues proposed AdsDR5 would enhance the prospects of using gene therapy for treating diseases of the liver, given the way it mitigated hepatocyte apoptosis.
The corresponding author for this study is J.D. Mountz, University of Alabama, Department of Medicine, Division of Clinical Immunology and Rheumatology, 701 South 19th Street, LHRB 473, Birmingham, AL 35294, USA.
Key points reported in this study include:
* Adenoviral-mediated delivery of gene therapy to the liver is difficult given the way immune system response factors target virally infected liver cells for destruction
* A novel vector, AdsDR5, neutralizes ligands and cytokines known to facilitate hepatocyte killing and diminish transgene expression
* The novel vector could enhance the use of gene therapies for treating liver diseases This article was prepared by Gene Therapy Weekly editors from staff and other reports.
To see more of the NewsRx.com, or to subscribe, go to http://www.newsrx.com.
Copyright 2002, Gene Therapy Weekly via NewsRx.com & NewsRx
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