Modified Virus Used To Treat Prion Disease In Mice

Main Category: CJD / vCJD / Mad Cow Disease
Article Date: 19 Jul 2008 - 2:00 PDT

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A treatment that prolongs survival in mice with prion disease has been found in research led by Dr Giovanna Mallucci at the Medical Research Council Prion Unit at UCL (University College London). Examples of prion diseases include vCJD and kuru in humans and BSE in cows. The results are published in PNAS.

Dr Mallucci and colleagues used a harmless form of virus carrying a specific strand of RNA to block production of prion protein in brain cells in mice with prion disease.

In prion diseases, a naturally occurring protein in the brain, known as prion protein (PrP), changes its normal shape when it comes into contact with misshapen versions of the same protein 'prions'. These abnormally shaped proteins build up in the brain and are infectious: once they start to accumulate they convert more and more of the normal PrP into the abnormal form, also known as PrPSc. This conversion process is associated with malfunction of brain cells, eventually leading to their death. These changes cause the symptoms of prion disease.

Past research at the Prion Unit and elsewhere has shown that normal PrP is a valid therapeutic target for prion disease, because if naturally occurring PrP is absent, prions cannot replicate and the PrPSc form cannot accumulate. Dr Mallucci's group set the scene for this new treatment in the past by showing that mice genetically engineered to stop making normal PrP recovered from prion disease when normal PrP production was switched off in infected mice.

Now the team has turned this approach into a treatment that does not depend on genetic changes in the whole animal. They have shown that by using a modified virus expressing a small sequence of RNA (shRNA) that binds to the PrP RNA in brain cells, the production of PrP can be blocked. The virally-expressed shRNA interrupts the normal process of translation of RNA into protein molecules in a process known as RNA interference.

The team gave a single one-off injection of the virus into a specific brain region in mice that had early prion infection. Blocking PrP production in this way in mice with established prion disease was found to have two effects. Firstly, the mice given the virus carrying RNA lived on average 19% longer than mice given a virus with no RNA and 24% longer than mice given no treatment at all. Secondly, the treatment prevented the onset of behavioural problems associated with early prion disease, and showed protection against degeneration of brain tissue and the loss of neurones.

Commenting on the significance of the finding Dr Mallucci said:

''The results are exciting because they have proved that tackling PrP even in a very focal way is beneficial in prion disease, protecting brain cells and extending survival in this model. Clearly, there is an issue with delivery of such treatments to a much larger organ such as the human brain and we don't know how much brain tissue would need to be targeted. These injections target tiny volumes of brain tissue. Getting the virus to a much larger brain area is a major goal for all gene therapy for neurodegenerative diseases. These results help us to answer other questions using this approach, which may help us to understand how to tackle these diseases with other forms of treatment also. Using this approach we can explore whether there are critical areas to be targeted in prion disease, how much of the brain needs to be targeted and understand the timing of such treatments.''

''This does not represent a realistic treatment for human patients, but it backs approaches of all types aimed at taking out normal PrP and should help us understand the timing and extent of delivery needed for effective treatments in future,'' Dr Mallucci concluded.

Original research paper: Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease by White et al is published in the journal PNAS.

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