Biomedical research

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Vectors used in gene therapy

Gene medicines typically consist of the gene product and a vector. The function of the vector is to get the new gene to the right destination in the cells’ DNA. Viral vectors remain by far the most popular approach, having been used in about two-thirds of the trials performed to date.

  1. Viral vectors 
  2. Retroviruses 
  3. Q vectors 
  4. Adenoviruses 
  5. Non-viral vectors 
  6. ‘naked’ DNA


1. Viral vectors

Crippled viruses are often used as a transportation vehicle. Crippled in this case means that the viruses that are used for gene therapy are made harmless by scientists. They replace the viral genes that cause disease with the genes that need to be delivered. Viral vectors can be the cause of adverse effects, when the patients’ immune system recognizes the viral particles and attacks it.

 

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2. Retroviruses

One of the consequences of the serious adverse events in the French SCID trial is a decrease in the proportion of trials using retroviruses. Retroviral vectors were the first vectors used in gene therapy but are now used in only 21.7% of the trials (28% in 2004). They target dividing cells with a high degree of efficiency and provide stable gene transfer, as they integrate into the genetic material of the target cell.

The main drawback of the use of retroviruses is related to this latter property. Research prompted by the serious adverse events in the French SCID trial has shown that the insertion pattern of these viruses is not random, and their preference for the first part of genes which can be activation sites is a cause for concern, because this can increase the risk on developing cancer like leukaemia.

 

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3. Q vectors

Self inactivating (SIN) retroviral vectors, also called Q vectors, are engineered so that activation of the target gene can only be driven by an internal starter signal once the expression cassette is integrated into the genetic material. The self-inactivation of the retroviral vector minimizes the risk that replication-competent retrovirus (RCR) will emerge.

It also reduces the likelihood that cellular coding sequences located adjacent to the vector integration site will be aberrantly expressed. These vectors should therefore avoid problems of incidental activation of endogenous cancer causing genes (oncogenes).

 

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4. Adenoviruses

Adenoviruses are now the most commonly used vector (24.9% of all trials). Adenoviruses can carry a larger DNA load than retroviruses but their capacity is still too small to accommodate the genes required for certain clinical applications.

The main advantages of adenoviral vectors are their high efficiency of delivering genes into cells and high level of gene expression, though this is transient and declines fairly rapidly, because the gene is not integrated into the cells genetic material. They also have the advantage of being able to infect non-dividing cells.

There are, however, important safety issues regarding adenoviral vectors, the main one being the possibility of provoking a severe immune and inflammatory response, as was tragically exemplified in the case of a death in a trial for OTC deficiency.

Other viruses have been less widely used and include vaccinia virus (8.2% of trials), poxvirus (6.1%), adenoassociated virus (4.1%), and herpes simplex virus (3.2%). The use of these vectors has increased significantly as alternatives to retroviruses are being explored.

 

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5. Non-viral vectors

The limitations of viral vectors, in particular their relatively small capacity for therapeutic DNA, and safety concerns have prompted the development of synthetic vectors not based on viral systems.

 

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6. ‘naked’ DNA

The simplest non-viral gene delivery system uses ‘naked’ DNA, which when injected directly into certain tissues, particularly muscle, produces significant levels of gene expression, though lower than those achieved with viral vectors. The popularity of naked DNA has increased (18.3% of all trials, 14% in 2004), possibly due to the concerns with regard to use of retrovirus.

Naked DNA is the most popular non-viral system used in clinical trials, followed by lipofection,which involves cationic lipid/DNA complexes (used in 7.1% of all trials).

There have been 35 trials that used two vectors, 28 used poxvirus and vaccinia virus, 3 used adenovirus and retrovirus, 2 used adenovirus and vaccinia virus, and 2 used naked DNA and adenovirus.

 

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