A fruitful marriage of gene therapy vectors
By combining the properties of two entirely different classes of virus, scientists may have stumbled upon a new way to deliver therapeutic genes to cells that significantly extends the length of time the gene is expressed. Bruce Baum and his colleagues have engineered an adenovirus vector with retroviral DNA sequences that enable therapeutic genes to be integrated in host chromosomes, allowing genes to be expressed far longer than with conventional adenoviruses. While the mechanism by which the viruses integrate is unclear, the approach may be useful in designing adenoviral gene therapies for inherited genetic disorders, which required prolonged expression of the therapeutic gene.
Derived from a causative agent of the common cold, adenoviruses are often used as gene therapy vectors in clinical trials. They are relatively easy to produce, capable of infecting quiescent or adult cells, and infect cells with high efficiency. A major disadvantage, however, is their inability to integrate into host cell DNA, which means that expression of the therapeutic gene can often be unstable and short lived. Retroviruses, on the other hand, are adept at integrating their DNA into the chromosome of host cells, which can be an advantage if long-term expression is required, such as for the treatment of inherited genetic disorders. To get around this problem, Bruce Baum and his colleagues have incorporated long terminal repeats (LTRs) from a mouse retrovirus into a standard adenoviral vector. Normally, these LTRs mediate retroviral integration in a reaction performed by the retroviral structural proteins, Env, Gag and Pol. Surprisingly, Baum and his colleagues found that the modified adenoviral could integrate a test gene into the host cell genome and drive its expression for far longer than previously shown, even in the absence of these retroviral structural proteins. Genetic analysis revealed that the vector was integrating into many different locations in the host cell chromosomes, but the mechanism of viral integration remains somewhat of a mystery.
Although the hybrid virus is far from application in the clinic, it seems likely that the authors may have found a new strategy for vector integration that could find application in other viral and even nonviral vector systems.
Contact
(Author)
Dr. Bruce J. Baum
NIDCR NIH
Building 10, Room 1N113
10 Center Drive
Bethesda MD 20892-1190
Tel: 301 496 1363
Fax: 301 402 1228
Contact
(Research News & Views)
Dr. Charles J. Link
Human Gene Therapy Research Institute
1415 Woodlan Ave.
Des Moines, IA 50309
Tel: 515 241 8787
Fax: 515 241 8788
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