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Viral Vector Delivery

Posted by Ares Wednesday, December 1, 2010

The initial strategies for gene therapy involved the construction of viral vectors in which the expression vector was packaged into a virus particle that was capable of invecting cells. The premise of developing viral vectors was that it might be possible to exploit, for therapeutic purpose, the highly evolved ability of viruses to introduce their genes into certain cells.
To do this, strategies were developed for constructing attenuated or defective

viral vectors that were capable of carrying therapeutic genes into cells but
were incapable of further propagation in patients, and were incapable of inducing viral pathogenesis. Many different viruses have been proposed as vihicles for vector delivery, and most of the clinical trials performed to date employ viral vectors.
The viruses which have been most extensively studied for gene therapy are retroviral vectors derived from the murine leukemia virus. To date, more than 100 patients have been treated with such virus in clinical trials. These viruses have several properties that have been exploited for gene therapy. The most important is that it is possible to construct completely defective viruses which carry therapeutic genes but do not encode any viral proteins. This is done using a packaging cell line that provides all of the proteins necessary to assemble a viral particle. If a packaging signal is incorporated into the vector and the vector is introduced into the packaging cell line, then the vector will be packaged inside the otherwise empty particle produced by the cell line. The defective retrovirus produced by these cell lines is stillcapable of infecting cells and stably integrating the vector into the chromosomes of the host cell. The methods for producing defective retrovirus have been described in detail elsewhere.
Because retroviral vectors are commonly produced in relatively low concentration and have a relatively low infectivity, these viruses are commonly employed in ex vivo strategies for gene therapy. Ex vivo therapy involves removing cells from a patient by a surgical procedure, growing these cells in the laboratory, infecting them with the retroviral vector, and then returning these cells to the patient by autologous transplantation. While the ex vivo strategy is well suited for certain targets such as bone marrow or lymphocytes where autologous transplantation is well established, it is less well suited to many solid organs in which clinically tested methods for cellular transplantation are incompletely developed. The recent work of Wilson and colleagues demonstrates that this method may be used to introduce genes into the liver of animals and patients at low prequency and may have a metabolic effect.
There is longstanding concern about the safety of retroviral vectors due to concern that the defective, therapeutic vectors may spontaneously recombine with naturally occurring retrovirus in the environment to give rise to new pathogens and to the risk associated with inserting a novel gene randomly into the genome, where it may disburb essential functions or activate proto-oncogenes. An additional limitation of retroviral gene therapy is the requirement for reflication of the target cell. Nondividing cells of many target organs are thus not appropriate targets for this form of gene therapy unless it is possible to safely stimulate replication. Nevertheless, retroviral vectors are currently important vehicles for vector delivery, and it is likely that additional clinical trials will begin to further evaluate their therapeutic potential.
Another vector which has been studied extensively and has entered clinical trials is the adenovirus. Adenoviruses have become an important research tool since it is possible to generate large numbers of viral perticles, infect virtually any cell (dividing or nondividing) by direct administration in vivo, and achieve high levels of gene expression. Unlike retroviral vectors, adenoviral vectors are not completely defective, but are merely attenuated by removing certain pathogenic determinants. Also unlike retroviruses, genes delivered by adenoviruses do not persist indefinitely within the cell, but commonly exhibit a half-life of several weeks to months. The limitation of adenoviruses for clinical use relates to the fact that the current generation of adenoviral vectors exhibits substantial cytopathicity and immunogenicity, which may provide a narrow therapeutic index and make them unsuitable for routine clinical use. Moreover, the immunogenicity observed after i.v. administration of adenovirus may prohibit the repetitive dosing which would be required to treat chronic disease.
Many other viruses exhibit selective properties that are attractive for gene therapy and have been proposed as potential vehicles for vector delivery. These include the adeno-associated virus, which may be able to insert its genes into a select location in the genome rather than a random location ;like the retrovirus, as well as herpesvirus, which may be able to achieve latency in various cells providing an extended period of gene expression. Research in many centers is aimed at reengineering these viruses into safe vehicles for vector delivery.

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