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
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A key problem in gene therapy is the lack of a vector system that fulfils all the requirements for safety and efficacy.
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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.
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Immunological barriers are a problem for all vectors, but particularly for adenoviral vectors.
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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.
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The next phase of gene therapy will be focused on targeted and regulated expression of the therapeutic gene.
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NIH recombinant DNA advisory committee meeting 8–10 March, 2000
Glossary
- LIPOSOMES
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Artificial lipid vesicles. Liposomes fuse with the cell membrane to deliver their contents, such as DNA for gene therapy.
- EPISOMES
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DNA molecules that are maintained in the nucleus without integrating into the chromosomal DNA.
- TRANSDUCTION
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The introduction of a gene into a target cell by a viral vector.
- INTERNAL RIBOSOME ENTRY SITE
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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.
- HAEMATOPOIESIS
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The programme of cellular differentiation leading to the formation of blood cells.
- KARYOPHILIC
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Literally, attracted to the nucleus — a nuclear localization signal in a protein is karyophilic.
- TROPISM
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The range of cells that can be productively infected by a virus.
- CAPSID
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The proteinaceous coat surrounding a virus.
- RESTENOSIS
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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.
- MEMORY CELLS
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Immune cells that are primed, after an initial exposure to an antigen, to make a rapid response to subsequent exposure to the same antigen.
- SEROTYPES
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Antigenically distinct forms that elicit different antibody responses by the immune system.
- DENDRITIC CELLS
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These cells present antigen to T cells, and stimulate cell proliferation and the immune response.
- TOLERANCE
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The lack of an immune response to a specific foreign protein.
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Somia, N., Verma, I. Gene therapy: trials and tribulations. Nat Rev Genet 1, 91–99 (2000). https://doi.org/10.1038/35038533
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DOI: https://doi.org/10.1038/35038533
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