The Adenovirus As Gene Therapy Vector

Our understanding about the biology of the adenovirus has increased enormously in the last decades, and today this virus is commonly used as a vector for gene transfer.[1] This knowledge about the adenovirus has led to a fast progression in the development of new gene therapeutic agents. The adenovirus is known for its efficient infection of dividing and nondividing cells, resulting in an efficient delivery of therapeutic genes to the site of action. Other advantages for the use of adenoviral vectors are the possibility to produce these viruses in very high titers and that they are relatively harmless.

To increase the safety measurements of adenoviral vectors in gene therapy, most adenoviral vectors used are unable to replicate. This elimination of replication is caused by the deletion of the E1A and E1B region of the adenoviral genome. This region is necessary for the adenovirus to replicate. The E3 region of the adenoviral genome may also be deleted to increase the space in the genome available for the insertion of transgenes up to 7.5 kb. The E3 region is not required for replication of the adenovirus, but includes genes that are able to interfere with the defense system of the host cell after infection.

Currently, the realization that clinical applications of adenoviral vectors encounter limitations becomes more and more clear. Although adenoviruses are among the most efficient vectors used in gene therapy, they are not always efficient enough. This is especially true for cancer gene therapy, where it is necessary to kill every tumor cell, otherwise the malignant tissue will reoccur. One intratumoral injected dose of adenoviral vectors will infect maximally 10% of the tumor cells, thus the therapeutic effect will be limited. Another major limitation of adenoviral vectors is the biodistribution of the adenovirus. When administrated intravenously, the majority of the virus ends up in the liver, where it can cause severe liver toxicity. Therefore a large proportion of research is conducted on the untargeting of the liver.

There are two main routes to untarget the liver and to achieve the specific gene therapeutic effect in particular sites of the body. The first one is transductional retargeting and the second one is transcriptional retargeting. Trans-ductional retargeting changes the cell entry route of the virus, whereas transcriptional retargeting restricts the expression of genes to the target cells (Fig. 1).

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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