Gene therapy is the introduction of a gene into cells to reverse a functional defect caused by a defect in a host genome (the set of genes present in an organism).
The use of viruses quickly became an attractive possibility once the possibility of gene therapy became apparent. Viruses require other cells for their replication. Indeed, an essential feature of a virus replication cycle is the transfer of their genetic material (deoxyribonucleic acid, DNA; or ribonucleic acid, RNA) into the host cell, and the replication of that material in the host cell. By incorporating other DNA or RNA into the virus genome, the virus then becomes a vector for the transmission of that additional genetic material. Finally, if the inserted genetic material is the same as a sequence in the host cell that is defective, then the expression of the inserted gene will provide the product that the defective host genome does not. As a result, host defective host genetic function and the consequences of the defects can be reduced or corrected.
Retroviruses contain RNA as the genetic material. A viral enzyme called reverse transcriptase functions to manufacture DNA from the RNA, and the DNA can then become incorporated into the host DNA. Despite the known involvement of some retroviruses in cancer, these viruses are attractive for gene therapy because of their pronounced tendency to integrate the viral DNA into the host genome. Retroviruses used as gene vectors also have had the potential cancer-causing genetic information deleted. The most common retrovirus that has been used in experimental gene therapy is the Moloney murine leukaemia virus. This virus can infect cells of both mice and humans. This makes the results obtained from mouse studies more relevant to humans.
Adenoviruses are another potential gene vector. Once they have infected the host cell, many rounds of DNA replication can occur. This is advantageous, as much of the therapeutic product could be produced. However, because integration of the virally transported gene does not occur, the expression of the gene only occurs for a relatively short time. To produce levels of the gene product that would have a substantial effect on a patient, the virus vector needs to administered repeatedly. As for retroviruses, the adenoviruses used as vectors need to be crippled so as to prevent the production of new viruses.
Adenovirus vector has been used to correct mutations the gene that is defective in cystic fibrosis. However, as of May 2002, the success rate in human trials remained low. In addition, the immune response to the high levels of the vector that are needed can be problematic.
Another important aspect of gene therapy concerns the target of the viral vectors. The viruses need to be targeted at host cells that are actively dividing, because only in cells in which DNA replication is occurring will the inserted viral genetic material be replicated. This is one reason why cancers are a conceptually attractive target of virus-mediated gene therapy, as cancerous cells are dangerous by virtue of their rapid and uncontrolled division.
Cancerous cells arise by some form of mutation. Therefore, therapy to replace defective genes with functional genes holds promise for cancer researchers. The target of gene therapy can vary, as many cancers have mutations that direct a normal cell towards acquiring the potential to become cancerous, and other mutations that inactivate mechanisms that function to regulate growth control. Furthermore, gene therapy can be directed at the immune system rather than directly at the cancerous cell. An example of this strategy is known as immunopotentiation (the enhancement of the immune response to cancers).
A risk of viral gene therapy, in those viruses that operate by integrating genetic material into the host genome, is the possibility of damage to the host DNA by the insertion. Alteration of some other host gene could have unforeseen and undesirable side effects. The elimination of this possibility will require further technical refinements. Adenoviruses are advantageous in this regard as the replication of their DNA in the host cell does not involve insertion of the viral DNA into the host DNA. Accordingly, the possibility of mutations due to insertion do not exist.
The September 1999 death of an 18 year old patient with a rare metabolic condition, who died while receiving viral gene therapy, considerably slowed progress on clinical applications of viral gene therapy.
See also Biotechnology