Retargeting Of Adenoviral Vectors

The adenovirus contains a protein capsid with protruding fibers. These fiber proteins form a trimer and the C-terminal region of these fibers is called the fiber knob. The fiber knob recognizes and binds to the host cell via the coxsackievirus-adenovirus receptor (CAR), which is present on many cell types. Upon binding to CAR, secondary interactions between the adenovirus and cell surface receptors cause the internalization of the adeno-virus. By shielding or modifying the fiber of the adenovirus, the native tropism can be altered. One possibility is to construct bispecific antibodies that on one side bind to the adenoviral fiber knob and on the other side will bind to an antigen present on target cells. This way, the adenovirus will be retargeted to cells that express this specific antigen. A second possibility is to construct

Fig. 1 To achieve transgene expression specifically in the tissue of interest it is possible to either change the homing of the virus (transductional retargeting) or to alter the expression profile of the transgene (transcriptional retargeting). (View this art in color at www.dekker.com.)

Fig. 1 To achieve transgene expression specifically in the tissue of interest it is possible to either change the homing of the virus (transductional retargeting) or to alter the expression profile of the transgene (transcriptional retargeting). (View this art in color at www.dekker.com.)

an adenobody, fusing an antibody directed against the fiber knob with a ligand for a receptor present on the cell type of interest. A third possibility to modify the tropism of the adenovirus is to genetically alter the fiber knob itself. It is possible to genetically insert sequences to be expressed within the fiber knob that are recognized by a certain receptor present on the cell type of interest without modifying the interactions within the trimer itself. However, it has to be noted that although interactions between the CAR receptor and the adenoviral fiber knob play an important role in cell uptake in vitro, these interactions might not play a crucial role in vivo.[2] Adenoviral particles containing a mutation within the fiber knob which abolished binding to the CAR receptor were systemically administrated in nonhuman primates. Surprisingly, the biodistribution of this ablated adenovirus was similar compared to the nonmodified adenovirus. This study showed that other receptors such as the heparan sulfate glycosaminoglycans (HSG) might play an important role in liver uptake. The construction of an adenovirus which is ablated for interactions between the virus and the HSG receptors can be a promising way to untarget the liver. Another approach to prevent uptake by the liver is PEG-ylation of the adenovirus.[3] Coating of the adeno-virus by polyethylene glycol (PEG) will shield the adeno-virus and prevent uptake by the liver. It is feasible to bind a homing device onto the PEG. This way the PEG-ylated adenovirus will be directed to the site of interest.[3]

Besides transductional retargeting of the adenovirus to the tissue or cell type of interest, it is also possible to transcriptionally retarget the adenoviral vector. Transcrip-

tional retargeting is the modification of the transgene expression profile to increase the specificity of gene transcription towards a certain tissue or cell type. Such increased specificity can be obtained by placing the gene of interest under control of a tumor- or tissue-specific promoter. This way, the gene of interest will only be transcribed in cells where the promoter is active.

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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