Gene silencing fights mad cow disease

22:00 01 December 2006
NewScientist.com news service
Roxanne Khamsi

Silencing the genes that produce prion proteins can dramatically slow the progression of mad cow disease, suggests a new study in mice.

Researchers say that the approach might one day work to treat human prion illnesses, such as variant Creutzfeldt Jakob Disease (vCJD).

People can contract vCJD after eating meat contaminated with mad cow disease. Though the illness is extremely rare, it can lead to schizophrenia-like psychosis and typically causes death within a year of diagnosis.

While doctors can prescribe drugs to temporarily treat some of the symptoms of prion disease, which include seizures, they still have no way to stop the progression of the illness.

Alexander Pfeifer at the University of Bonn in Germany, and colleagues, explored the possibility of fighting prion disease in mice using a method of gene silencing known as RNA interference (RNAi).

Embryo virus
This method exploits messenger RNA (mRNA) sequences in the cell, which are responsible producing proteins by using the animal’s genetic code as an instruction list. RNAi relies on molecules that bind to mRNA sequences in the cell, thereby preventing the production of specific proteins.

The researchers used a harmless virus to carry RNAi code into the mouse cells, which specifically disrupts the mRNA sequences that produce normal prion proteins.

When simply injected into the bloodstream these viral agents do not easily reach brain cells – those most affected by prion disease. So researchers exposed mouse embryos to the virus. Because the embryonic cells took up the virus at an early stage, many of the brain cells they generated contained the RNAi code..

Longer life
Pfeifer and his collaborators, including Hans Kretzchmar at the University of Munich, Germany, then injected the brains of the mice with infectious “scrapie” prions from sheep. The mice with the highest proportion of brain cells containing RNAi code – roughly 85% – lived about 230 days after infection. Normal mice, by comparison, typically died within 170 days.

Researchers say the RNAi worked because it reduced the production of normal prions, which are thought to become miss-folded and dangerous after coming into contact with infectious prions.

Pfeifer notes that delivering RNAi to patients remains a challenge. He says that researchers are now conducting animal tests to see if the engineered viruses that prevent prion production can be delivered straight to the brain through a catheter.

Vaccine approach
Other approaches currently being developed to fight prion disease, such as a vaccine, would be much easier to administer if they prove successful, according to Qingzhong Kong of Case Western Reserve University in Cleveland, Ohio, US (see Two vaccines show promise against prion disease).

Kong says there is a danger that the harmless virus used in an RNAi could mix with a patient infected with another retrovirus, such as HIV. In a worst-case scenario, this kind of recombination could potentially give rise to a more aggressive form of HIV, he warns, which could in theory then be passed on.

Experts also say that stopping prion production could have unintended side effects. Recent studies have suggested that these proteins help new nerve cells form (see When prions are 'good for the brain'). But Kong says that even if anti-prion RNAi does slow nerve formation to some degree, this side effect is preferable to the fatal consequences of vCJD.

Journal: Journal of Clinical Investigation (DOI: 10.1172/JCI29236)