ASGT Press Release

This is the press release for the March 2002 issue of Molecular Therapy, the Journal of the American Society of Gene Therapy. Molecular Therapy is published monthly by Academic Press, an imprint of Elsevier Science. Please credit Molecular Therapy as the source of this information. The embargo is lifted upon your receipt of this message. All questions should be directed to the editor (see below). If you have a colleague who would like to receive this release, please have them email the editor directly.

Evading Immunity I: Slipping past antibodies

(cover photo - electron micrograph of liposome-coated adenovirus)
("Bilamellar cationic liposomes protect adenovectors from preexisting humoral immune responses." P. Yotnda, et al. (2002). Molecular Therapy 5: 233-241.)

Adenovirus vectors, the most widely used gene therapy tool to date, can be rendered ineffective or worse by the presence of preexisting adenovirus antibodies in the recipient. Furthermore, their effectiveness depends on the appropriate receptor for adenovirus on the target cells of interest.

In this issue, Patricia Yotnda and her colleagues at the Baylor College of Medicine in Houston describe an adenoviral "camouflage" that not only can evade the humoral immune response but can also help adenovirus enter cells that are normally resistant to adenoviral infection. They describe the results of experiments in which they coated adenoviral vectors with bilamellar liposomes, which have been used before to deliver simple plasmid DNA to cells. The coated adenovectors are stable in human serum, evade the humoral response, and infect a wider range of cells. Furthermore, the effectiveness of adenovirus infection was increased over previous methods, suggesting that lower doses could be used, thus limiting the toxicity that has been seen in both preclinical and clinical experiments.

Evading Immunity II: Taming T cells

("Prolongation of transgene expression by coexpression of cytokine response modifier A in rodent liver after adenoviral gene transfer." X.-K. Li, et al .(2002). Molecular Therapy 5: 262-268.)

Even if adenoviral vectors successfully evade the humoral immune response and successfully infect target cells, the cellular immune response will often kick in to remove the infected cells. Hepatocytes, which are desirable targets for systemic gene therapy, are encouraged to apoptose (die) following infection through a Fas-mediated mechanism, thus limiting  the duration of transgene expression. One way around this problem may be to interfere with the usual cell-death signal sent by activated T cells.

To this end, Torayuki Okuyma of the Kyoto School of Medicine and collaborators designed experiments to test if the co-expression of a transgene of interest along with a gene that interfered with the cellular immune response would prolong the expression of the transgene delivered by an adenoviral vector. They designed an adenovirus containing the gene encoding beta-glucuronidase (GUSB, the missing enzyme in one form of mucopolysaccharidosis) and the gene encoding cytokine response modifier A (CrmA, a molecule that can block the Fas-mediated apoptosis) and injected it into mice lacking beta-glucuronidase. The expression of CrmA to tame the cellular immune response dramatically increased the duration of expression of GUSB over controls, suggesting that this approach could be used in a clinical setting to both reduce toxicity (i.e., less adenovirus would be required) and prolong expression of a curative gene.

Gene Regulation I: Antibiotic Control of Gene Expression

Tet-a-Tet
("Robust and efficient regulation of transgene expression in vivo by improved tetracycline-dependent lentiviral vectors. E. Vigna, et al. (2002). Molecular Therapy 5: 252-261.) 

A significant problem facing most gene therapy vectors is the lack of control over timing and amount of transgene expression. This is particularly critical in considering treatments where the missing protein is normally under very tight control. Towards this goal, Luigi Naldini of the University of Torino Medical School in Candiolo, Italy, and his collaborators describe the development of a series of effective and tightly regulatable vectors. Based on the latest generation of lentiviral vectors (a very promising gene therapy vehicle), the researchers modified the regulatory part of the vectors to render the transgene expression under total control of tetracycline-responsive promoters. A range of vectors is described for many different applications. To prove the robustness of their vectors, Naldini and coworkers apply them to hematopoietic cells and tumors, two major gene therapy targets and ones in which transgene expression must be managed, and show that they can achieve tight control in an in vivo model of both.

Gene Regulation II: Steroid Control of Gene Expression

Knowing when to stop
(" Glucocorticoid-regulated VEGF expression in ischemic skeletal muscle." I. Hallaby et al. (2002). Molecular Therapy 5: 300-306.)

Vascular endothelial growth factor (VEGF) is a potent angiogenic molecule and a promising agent for stimulating the growth of new blood vessels following ischemic injury in heart or skeletal muscle. However, prolonged expression of VEGF could cause more problems than it solves. Thus eventual clinical use will require tight control of the VEGF gene therapy vector.

In this issue, William Bowers of the University of Rochester School of Medicine and Dentistry and his colleagues describe the novel use of a plasmid vector containing the VEGF gene under the control of a glucocorticoid-responsive element. The researchers injected the plasmid into the hindlimb muscle of rabbits that had undergone experimental ischemia of the muscle before treatment with the vector. Following injections, the rabbits were given the dexamethasone (DEX), a synthetic glucocorticoid. DEX treatment increased VEGF expression (and new blood vessel growth) and withdrawal of DEX led to diminished expression and slowed vessel growth. This kind of control has direct implications for angiogenic gene therapies of both heart and skeletal muscle, as well as providing a tool for the further study of muscle-specific biological processes.

Other items of interest:

Editorial: A Gene Therapy Institute for NIH?
Editor-in-Chief Inder Verma of the Salk Institute argues that it may be time to consider a new Institute of Gene Therapy Research at the National Institutes of Health to focus on specific issues in the field.

Articles:

A preventive/therapeutic melanoma vaccine
"Induction of a systemic immune response by a polyvalent melanoma-associated antigen DNA vaccine for prevention and treatment of malignant melanoma." Tanaka et al. (2002). Molecular Therapy 5: 291-299.

SIV vectors for human use
"High levels of transduction of human dendritic cells with optimized SIV vectors." Mangeot et al. (2002). Molecular Therapy 5: 283-290.

Methods:

Double-duty gene delivery
"A syringe electrode device for simultaneous injection of DNA and electrotransfer." Liu and Huang. (2002). Molecular Therapy 5: 323-328.

Fintan R. Steele, Ph.D.
Editor, Molecular Therapy
Executive Editor, Genomics
Academic Press
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fsteele@acad.com
http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC
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