Nucleic-acid- and cell-based therapeutics - Pharmaceutical Biotechnology: Concepts and Aapplications - page 446

A different gene therapy-based approach to cancer entails introduction of a gene into
haematopoietic stem cells in order to protect these cells from the toxic effects of chemotherapy.
Most cancer drugs display toxic side effects which usually limits the upper dosage levels that can
be safely administered. One common toxic side-effect is the destruction of stem cells. If these cells
could be protected or made resistant to the chemotherapeutic agent, it might be possible to admin-
ister higher concentrations of the drug to the patient. In practice, such a protective effect could be
conferred by the multiple drug resistance (type 1; MDR-1) gene product. This is often expressed
by cancer cells resistant to chemotherapy. It functions to pump a range of chemotherapeutic drugs
(e.g. daunorubicin, taxol, vinblastine, vincristine, etc.) out of the cell. Animal studies have con-
fi rmed that introduction of the MDR-1 gene into stem cells protects these cells subsequently from
large doses of taxol. This approach is now being appraised in patients receiving high-dose chemo-
therapy for a range of cancer types, including breast and ovarian cancer and brain tumours.
14.6 Gene therapy and AIDS
It is likely that gene therapy will prove useful in treating a far broader range of medical conditions
than simply those of inherited genetic disease and cancer. A prominent additional disease target
are those diseases caused by infectious agents, particularly intracellular pathogens such as HIV.
The main strategic approach adopted entails introducing a gene into pathogen-susceptible cells
whose product will interfere with pathogen survival/replication within that cell. Such a strategy is
sometimes termed 'intracellular immunization'.
One such anti-AIDS strategy being pursued is the introduction into viral-sensitive cells of a gene
coding for an altered (dysfunctional) HIV protein, such as gag , tat or env . The presence of such mutant
forms of gag , in particular, was shown to be capable of inhibiting viral replication. This is probably
due to interference by the mutated gag product with correct assembly of the viral core. An additional
approach entails the transfer to sensitive cells of a gene coding for antibody fragments capable of
binding to the HIV envelope proteins. This may also interfere with viral assembly in infected cells.
Scientists have also generated recombinant cells capable of synthesizing and secreting soluble
forms of the HIV cell surface receptor, i.e. the CD4 antigen. It has been suggested that release of
such soluble viral receptors into the blood would bind circulating virions, hence blocking their
ability to 'dock' at sensitive cells. Although this proved to be the case in vitro , early in vivo
studies have not proved as encouraging. Yet additional therapeutic approaches to AIDS, based
upon antisense technology, will be discussed later in this chapter.
14.6.1 Gene-basedvaccines
Conventional vaccine technology, including the generation of modern recombinant subunit
vaccines, has been discussed in Chapter 13. An additional gene-therapy-based approach to
vaccination is also now under investigation. The approach entails the administration of a DNA
vector housing the gene coding for a surface antigen protein from the target pathogen. In this way,
the body itself would produce the pathogen-associated protein. Theoretically, virtually any body
cell could be targeted, the only requirement being that target cells export the resultant antigenic
protein such that it is encountered by the immune system. Additionally, gene expression need only
be transient, i.e. just suffi ciently long to facilitate the induction of an immune response. Target