Reference Work Entry

Encyclopedia of Cancer

pp 1523-1526


Gene Therapy

  • Valerie BoschAffiliated withForschungsschwerpunkt Infektion und Krebs, F020, German Cancer Research Center (DKFZ) Email author 


Directed introduction and expression of new genetic information in cells of an organism for therapeutic purposes. Only somatic gene therapy is presently permitted, and the introduction of genetic material into germ-line cells is not allowed.


The science of gene therapy has its beginnings in the early 1980s, subsequent to the identification of several disease-related genes and the development of technologies for gene isolation, purification, and transfer to cells in culture. Many different human diseases represent theoretical targets for gene therapeutic intervention and the strategies developed depend on the nature of the disease to be treated. Table 1 illustrates several classes of human disease and the respective treatment strategies currently being followed. It goes without saying that detailed knowledge of the molecular mechanisms of disease development and progression is a prerequisite for the development of gene therapeutic intervention strategies.
Gene Therapy. Table 1

Examples of gene therapeutic strategies for different disease groups

Disease group

Genetic basis of disease


Hereditary monogenic disease, e.g., hemophilia, cystic fibrosis

Defective gene which results in a single gene product being missing or nonfunctional

Introduction of wild-type gene (e.g., into liver or muscle for the production of a protein in the blood circulation, into lung in the case of cystic fibrosis)

Multifactorial disease, e.g., cardiac disease, diabetes

Many genes and their gene products directly or indirectly involved

At present too complex. However, restenosis. (i.e., tissue proliferation after surgical dilation of a blood vessel) can be treated by locally expressing genes which inhibit cell proliferation


Somatic mutation of cellular genes (several)

1. Induction of cell death employing genes encoding toxic gene products

2. Stimulation of the immune system to recognize and destroy cancer cells. (Cancer vaccinesDNA vaccination)

3. Inhibition of “cancer genes.” (Cell-cycle targets for cancer therapy)

4. Prevention of tumor angiogenesis

Infectious diseases, e.g., AIDS

New genetic material from the infectious agent (e.g., virus) induces pathogenic processes

1. Inhibition of expression of genes encoded by the infectious agent employing, e.g., antisense, ribozyme or small-interfering (si) RNA approaches. (Antisense DNA therapy)

2. Vaccination against viral gene products expressed from transferred heterologous viral vectors or from naked DNA, i.e., infection prevented or eliminated by the patient’s immune system

Transfer of Genes

Very many different methods have been developed to transfer therapeutic genes to patient cells. A consideration which is central to the choice of gene transfer vehicle (vector) is whether stable or only transient gene expression is required. Stable gene expression is necessary for the treatment of hereditary genetic defects whereas transient gene expression is sufficient, and may even be desirable, when employing genes encoding toxic gene products, e.g., in the treatment of cancer. Many gene transfer vehicles employ components of viruses (viral vector-mediated gene transfer) since viruses have evolved to efficiently transfer their own genes to cells and to express the respective gene products at high levels. Since it may not be possible to completely eliminate potential safety problems with viral vectors, nonviral gene transfer vehicles have been developed in parallel. These transfer vehicles are based on lipids/liposomes (lipoplexes), on polycations (polyplexes), on branched polymer structures (dendriplexes) or consist simply of naked DNA (Nonviral vectors for cancer therapy). In general, the transfer efficiencies and gene expression levels achieved with nonviral vectors are poorer than with viral vectors. The commonly used gene transfer vectors, their advantages and their disadvantages are summarized in Table 2.
Gene Therapy. Table 2

Gene transfer vehicles, their advantages and disadvantages

Gene vehicle



Retrovirus vectors including those based on lentiviruses

1. Integration of vector into host genome leading to stable gene expression

1. Titer not as high as, e.g., adenoviral vectors

2. No cellular toxicity

2. Vector integration into host genome is potentially mutagenic

3. Lentiviral vectors also infect (transduce) differentiated nondividing cells

Adenovirus vectors

1. Very high titers (1013/ml)

1. Only transient gene expression

2. Very high, but transient, gene expression

2. Immune response to vector and transgene

Adeno-associated virus (AAV) vectors

1. AAV is not pathogenic in humans

1. Lower coding capacity than with retroviral and adenoviral vectors

2. Nontoxic

2. Gene expression in proliferating tissue only transient

3. Infects nondividing cells

Lipoplexes, polyplexes, and dendriplexes

No viral genes, no toxic effects

Mostly lower and transient gene expression

Naked DNA

No viral genes, no toxic effects

Mostly lower and transient gene expression

In many situations, in addition to high gene transfer efficiency, it is necessary that the transfer vector is selective, i.e., mediates expression of the therapeutic gene exclusively in targeted diseased cells. Achieving selectivity is a major hurdle which is being approached in several ways. Gene vectors are being manipulated (on the surface of the gene vector particle) such that targeted cells are exclusively accessed. Selectivity can be achieved by ensuring that, even in the situation in which many cells have been accessed, expression of the therapeutic gene can only occur in specific targeted cells (e.g., by employing tissue-specific promoter/enhancer elements to control therapeutic gene expression).

Clinical Relevance

Therapeutic genes can be introduced into patient cells either ex vivo or in vivo (see Fig. 1). In the ex vivo application, a patient biopsy is genetically manipulated outside the body and subsequently reinjected or transplanted. This procedure has the advantage that only the cells in the biopsy come in contact with the transfer vector. Furthermore, the circumstances in cell culture generally allow more efficient gene transfer than on in vivo application. In addition, in some cases it is possible to expand the cells in the biopsy and create a pool of genetically modified cells which can be reapplied to the patient as required. The main disadvantage of the ex vivo procedure is that it is technically cumbersome, time consuming, and very expensive. The most straightforward and desirable situation would be to apply the gene transfer vehicle in vivo either directly into specific tissues or organs (e.g., directly into tumor tissue) or by injection into the blood circulation. In vivo application requires that the transfer vector efficiently reaches the appropriate diseased cells and at present, this is very often not the case. In fact, major problems hampering gene therapeutic approaches today concern the efficiency and the selectivity of the transfer vectors when applied in vivo. Further problems are related to the induction of host immune reactions toward the (viral) vector and the transgene.
Gene Therapy. Fig. 1

Application routes for gene therapy

Permission for the first clinical gene therapy study was granted in 1989 and since then numerous clinical trials, for the most part with only relatively small numbers of patients, have been carried out. Lack of sufficient selectivity and efficiency of transfer as well as lack of stability of transgene expression, the results of most of these trials did not establish any statistically verified positive effects on disease progression or mortality. Recently, however, more favorable results have been obtained. Thus, as a result of a gene therapeutic intervention with a retroviral vector, several individuals were cured of severe X-linked combined immunodeficiency. Unfortunately, however, within this same trial, severe adverse side effects were observed in three treated patients. In the meantime, the reasons for these adverse effects have been largely elucidated and subsequent protocols will be adjusted accordingly. At present, basic research is focused on improving gene vector properties and on gaining a better understanding of the interactions between the gene vector, the transgene, and the patient’s immune system. It is to be anticipated that the combined knowledge gained from these efforts will allow gene therapeutic protocols to be developed which will represent valid treatments for diseases which have been difficult or impossible to therapy up until now.

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© Springer-Verlag Berlin Heidelberg 2011
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