Gene therapy: trials and tribulations

The art and science of gene therapy has received much attention of late. The tragic death of 18-year-old Jesse Gelsinger, a volunteer in a Phase I clinical trial, has overshadowed the successful treatment of three children suffering from a rare but fatal immunological disease. In the light of the success and tragedy, it is timely to consider the challenges faced by gene therapy — a novel form of molecular medicine that may be poised to have an important impact on human health in the new millennium.

Key Points

  • A key problem in gene therapy is the lack of a vector system that fulfils all the requirements for safety and efficacy.

  • Viral vectors are the most promising vectors at this time. Integrating viruses are based on retrovirus, lentivirus and adeno-associated virus. Some vectors are based on adenovirus — a non-integrating virus.

  • Immunological barriers are a problem for all vectors, but particularly for adenoviral vectors.

  • The death of Jesse Gelsinger in a gene therapy Phase I clinical trial has overshadowed some recent successes in gene therapy in animal models and notably in humans with a form of severe combined immune deficiency.

  • The next phase of gene therapy will be focused on targeted and regulated expression of the therapeutic gene.

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Figure 1: Retrovirus-based vectors.
Figure 2: In vivo gene delivery into mice and rats using lentiviral vectors.
Figure 3: Adeno-associated viral vectors.
Figure 4: Regulation of gene expression.
Figure 5: Regulated expression of a gene therapy vector.


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OTC gene


γC cytokine receptor subunit


ADA gene

Haemophilia A

Haemophilia B

factor IX

factor IX knockout mice

haemophilic dogs


ecdysone receptors


NIH recombinant DNA advisory committee meeting 8–10 March, 2000

The Institute for Human Gene Therapy

Verma lab homepage



Artificial lipid vesicles. Liposomes fuse with the cell membrane to deliver their contents, such as DNA for gene therapy.


DNA molecules that are maintained in the nucleus without integrating into the chromosomal DNA.


The introduction of a gene into a target cell by a viral vector.


A sequence that is inserted between the coding regions for two proteins and allows efficient assembly of the ribosome complex in the middle of a transcript, leading to translation of the second protein.


The programme of cellular differentiation leading to the formation of blood cells.


Literally, attracted to the nucleus — a nuclear localization signal in a protein is karyophilic.


The range of cells that can be productively infected by a virus.


The proteinaceous coat surrounding a virus.


Stenosis is the blocking of a blood vessel that can be cleared by mechanical disruption. Restenosis is the recurrence of the blockage caused, for example, by unchecked proliferation and migration of vascular smooth muscle cells.


Immune cells that are primed, after an initial exposure to an antigen, to make a rapid response to subsequent exposure to the same antigen.


Antigenically distinct forms that elicit different antibody responses by the immune system.


These cells present antigen to T cells, and stimulate cell proliferation and the immune response.


The lack of an immune response to a specific foreign protein.

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