Progress and problems with the use of viral vectors for gene therapy

Key Points

  • Five main classes of clinically applicable virus vector have been engineered over recent years to improve the efficiency and safety of gene delivery. Hybrid vectors that combine the properties of different viral vectors are now being developed.

  • Each type of vector is characterized by a set of properties (and a set of problems) that make it suitable for some applications and unsuitable for others.

  • An important obstacle to the use of adenovirus vectors has been their immunogenicity. Highly disabled gene-deleted adenovirus vectors have been engineered to reduce toxicity and circumvent cytotoxic T-cell responses against transduced cells.

  • The risk of inducing oncogeneis through retrovirus integration is higher than was previously thought. This risk might be restricted to gene-therapy applications in which the clonal expansion of transduced cells is required.

  • Engineering vectors so that they target specific populations of cells after systemic vector delivery represents a serious challenge. A variety of approaches to 'transductional retargeting' are being investigated.

  • A continuing focus on vector development, and an emphasis on understanding vector–host interactions, will underpin the future success of gene therapy.

  • Particular areas of important research will include the exploitation of new viruses, the development of site-specific integrating vector systems, improvement of the efficiency with which vectors infect certain cell types, understanding how to predict the response of individuals to inflammatory vectors, and incorporating new technologies — such as RNA interference — into viral vector systems to extend the range of therapeutic applications.


Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

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Figure 1: Converting a virus into a vector.
Figure 2: A survey of gene transfer clinical trials.
Figure 3: Strategies to achieve targeted gene expression from adenovirus vectors.


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This work was supported by grants from the National Institutes of Health.

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Correspondence to Mark A. Kay.

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Journal of Gene Medicine Clinical Trial Database



A short non-coding DNA sequence found at each end of the viral genome, which contains elements required for the replication and packaging of the viral DNA.


A protein shell that encapsulates the viral genetic material.


Inappropriate blood clotting.


The introduction of genetic material into a cell using a viral vector.


A measure of vector concentration that is usually expressed as the number of transducing units, or the number of particles per millilitre.


A stable DNA molecule that persists in the nucleus without integrating into the cellular genome.


The range of cell types or tissues in which a virus can sustain a productive infection.


The alteration of the vector tropism by substitution of the virus receptor-binding proteins with those from other virus strains.


The first viral genes that are expressed after infection. Early-gene expression does not require de novo viral protein synthesis. Early-gene products activate viral DNA replication and the expression of viral structural proteins.


The first stage in a clinical trial, which is designed to assess only the safety and dosage levels of a new treatment and usually involves only a few patients.


The assessment of efficacy, usually on a small scale.


The assessment of efficacy and side-effects, which generally involves hundreds of patients from different clinics nationwide or worldwide.


A subset of antigen-presenting cells, which are particularly active in stimulating T cells.


Related members of the same virus species that are distinguishable by serological methods.


The direction of vector-mediated transgene expression to particular cell types by the alteration of vector tropism.


Facilitating fusion of the viral envelope with the cellular plasma membrane.


A gene that encodes a protein that can convert a non-toxic prodrug into a cytotoxic compound.


(NHEJ). One of two cellular DNA-repair pathways that are involved in the repair of double-strand breaks.

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Thomas, C., Ehrhardt, A. & Kay, M. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4, 346–358 (2003).

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