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Offline lara

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viral vectors
« on: 28/09/2005 12:20:46 »
can some1 tell me how do viral vectors  used in gene therapy cause cancer if their harmful genes r removed??


 

Offline chris

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Re: viral vectors
« Reply #1 on: 01/10/2005 13:16:04 »
Good question

Viruses are little more than infectious packets of genes. Without a plant, animal or bacterial cell they cannot reproduce because, at only 50-200 nm (that's about 1 ten thousandth of a millimetre across, on average), viruses are too small to carry the machinery required to reproduce. So instead they hijack cells and turn them into viral factories.

To do this means that they have to be highly efficient at recognising their target cell type (in other words the type of cell that best supports their growth), they must be able to penetrate that cell, and then express their own genes to alter the function of the host cell and turn it into a viral production line.

For these reasons, researchers view viruses as promising candidate gene delivery vectors since it may be possible to tame certain viruses, to prevent them from causing disease, and at the same time exploit their ability to home in specifically on certain cell types and alter their function.

A number of viruses have been tested in this respect including adenoviruses, herpes viruses, adeno-associated viruses (which borrow their surface coats from adenoviruses) and retroviruses (including HIV now).

Of these, the retroviruses and adeno-associated viruses have shown the greatest promise to date. This is because these viruses insert their genetic material into the host cell genome, which means that it is easier to maintain the expression of the therapeutic gene message that you wish to add to the target cell. In other words, genes inserted into the host genome tend to remain switched on for longer.

So far there have been a number of human clinical trials involving some of these viruses, the most often cited example being the use of retroviral vectors to treat a rare and often fatal immune disorder called SCID (severe combined immunodeficiency), one cause of which is inheriting  defective ADA (adenosine deaminase) genes.

Researchers were able to take immune cells from babies with this condition and infect the cells with a retroviral vector from which the genes enabling it to replicate (grow) had been removed and replaced with a healthy copy of the ADA gene. After treatment, the cells were re-infused into the SCID babies, who showed improvements in the function of their immune systems.

But the problem is that when viruses insert their genetic material into the host genome, a process called integration, they can sometimes accidentally switch on some of our own genes which are near to the integration site. The converse can also happen, and some genes can be inactivated by the arrival of the viral DNA.

If these genes happen to be growth factors, which are supposed to be switched off and are instead turned on, or they are anti-cancer genes and are accidentally turned off, then the infected cells can become more prone to becoming cancerous. This is referred to as insertional mutagenesis.

Also, the insertion of foreign genetic material into the host genome can cause the host DNA to become unstable and more prone to breakages which are also associated with malignant transformation (becoming cancerous).

There have since been cases of malignancies associated with prior retroviral vector therapy, but it might be possible to surmount these problems if a way can be found to ensure that the viruses only integrate in one specific genome site, which can be shown to be free from risk.

Adeno-associated viruses (AAVs), in their natural form, target their integration to a site on human chromosome 19 which seems to be free from problems since AAV infection has not been linked to cancer. Unfortunately, whilst AAVs can be turned into effective gene therapy vectors, replacing the normal viral genetic components with therapeutic genes causes the virus to lose its preference for chromosome 19 and instead integration becomes random again.

Aside from insertional mutagenesis, there are other risks associated with the use of viral vectors. Viruses contain foreign proteins and, as such, are capable of triggering powerful host immune responses, meaning the immune system then begins to attack the cells you are trying to 'treat'. It could also provoke an auto-immune disease whereby the virus fools the body into attacking healthy tissue because it shares some common surface chemical features with the virus. The other major concern is that the vectors we produce should be environmentally safe. In other words, once inside the body could the disabled 'therapeutic' virus meet up with a wild-type undisabled relative leading to a recombination event in which the two viruses swap a few genes to produce a fully virulent (infectious) virus that also contains a 'therapeutic' human gene. If this virus then escaped into the population at large, the effects would be unpredictable and potentially very dangerous.

So whilst the idea is a neat one, and certainly worthy of careful investigation, the field is fraught with difficulties and risks, so it is necessary to proceed with the utmost caution.

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx
 

Offline lara

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Re: viral vectors
« Reply #2 on: 04/10/2005 08:54:44 »
thanx a lot.but recombination in viruses???plz xplain a bit!!
 

Offline chris

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Re: viral vectors
« Reply #3 on: 11/10/2005 12:18:47 »
If you modify a virus to make it safe, for instance by removing an essential gene required for growth, and then adding a therapeutic gene - a neurotrophic factor to promote nerve regeneration for example - it's possible for a recombination event to restore the modified virus to full virulence creating a replicating virus bearing a human gene. The consequences would be at best unpredictable and at worst lethal.

Imagine you have injected your modified virus into a person to cure them of a disease. But then they naturally become infected with the wild-type relative of the virus you have used to make your gene therapy vector.

If the wild type virus and the modified virus infect the same cell the two viruses can swap genes creating a hybrid containing components of each. As a result the wild type virus could transfer back to your therapeutic vector the ability to replicate and spread to other people.

This would produce a replicating virus which is also carrying a human therapeutic gene. Whilst small amounts of that gene in the right place at the right time might be beneficial, large doses delivered indiscriminately might be fatal.

One way around this problem is to insert the therapeutic gene into the virus in place of one of its essential genes (those without which it cannot grow). This way, if such a recombination event does take place between the vector and a wild-type virus, the only way it can produce a replicating vector is if the therapeutic gene is lost (in order to restore the essential gene).

Chris

"I never forget a face, but in your case I'll make an exception"
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Re: viral vectors
« Reply #3 on: 11/10/2005 12:18:47 »

 

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