Experimental treatment could work against prion diseases like CJD

An experimental therapy has dramatically extended the lives of mice infected with prions, which cause conditions like Creutzfeldt–Jakob disease (CJD). The news, announced by Sangamo Therapeutics, boosts hopes of developing treatments for these conditions.

“Mice die very rapidly if they are not treated. The average lifespan of the mice that are treated is starting to extend over 500 days, which is kind of the normal lifespan,” says Jason Fontenot at Sangamo Therapeutics. “It’s very effective.”

Prion diseases are unusual in that they are caused by a misfolded protein that makes other proteins of the same kind misfold too and join up to form damaging strand-like fibrils in cells. Fragments of fibrils spread the problem to other cells.

This causes serious damage to the brain, with death usually occurring within a year of the first symptoms. “It’s a devastating disease,” says Fontenot.

Some forms of CJD are caused by eating contaminated food such as meat from cattle with BSE (bovine spongiform encephalopathy), also known as mad cow disease, or by surgical instruments or blood contaminated by prions. Others are due to mutations that make misfolding more likely. But with most cases of CJD, there is no clear cause – they may be a result of spontaneous misfolding.

In almost every prion disease, the protein that misfolds is one called PrP. Its normal function isn’t clear, but mice and cows engineered so they can’t make PrP don’t seem to have any serious ill effects and they are immune to prion diseases because there is no PrP in their bodies to misfold.

So, efforts to develop treatments for CJD are focused on PrP. To do this, researchers at Sangamo Therapeutics created a protein that binds to a specific sequence of DNA near the gene that produces PrP and switches it off, preventing the protein from being made. A gene to make this turn-off-PrP protein can be delivered into brain cells using viruses selected for their ability to target neurons.

To test the treatment, the researchers infected mice with prions. Untreated mice developed symptoms about 120 days later and all died after around 160 days.

But mice lived much longer if they were given a single dose of the virus carrying the gene for the turn-off-PrP protein, with this treatment coming either 60 or 120 days after infection. Ten of these 19 mice were still alive 360 days post-infection, and five survived for 500 days, Sangamo Therapeutics revealed at a meeting of the American Society of Gene & Cell Therapy in Los Angeles in May.

“The work is encouraging,” says John Collinge at the Institute of Prion Diseases at University College London, whose team has developed another potential treatment based on antibodies that target PrP.

Sangamo Therapeutics is now tweaking the turn-off-PrP protein to target the human gene for PrP, and hopes to begin human trials soon, says Fontenot. In people, the viruses carrying the gene for the turn-off-PrP protein may need to be injected into spinal fluid or directly into the brain.