BioWorld International Correspondent
LONDON - It may one day be possible to treat prion diseases such as variant Creutzfeldt-Jakob disease (vCJD) by mopping up all the naturally occurring normal prion protein in the brain, a study in mice suggested.
Using a mouse model in which the animals' nerve cells stop expressing the native prion protein at about 9 weeks of age, researchers showed that animals with prion disease that previously showed behavioral abnormalities and impaired nerve signaling began to recover after that point.
The finding could help in the development of new therapies for vCJD, and possibly other diseases, which could be tested for efficacy using similar animal models.
Giovanna Mallucci, group leader and honorary consultant neurologist at the MRC Prion Unit and department of neurodegenerative disease at the Institute of Neurology in London, told BioWorld International: "The recovery of early behavioral and memory problems we see in this study gives hope that early behavioral and cognitive problems in humans might be reversible."
The findings are potentially exciting for neurodegenerative diseases in general, she added. "It is possible that there are common mechanisms of toxicity in many of these diseases. In prion therapy, we still need a drug or treatment that can do what we did here by genetic engineering to inactivate the prion protein, and critically, we need a test for early diagnosis in humans," she said.
The MRC Prion Unit currently is running a program for high-throughput screening of potential drugs to target prion protein; other research is exploring a gene therapy approach.
Mallucci cautioned that although depleting prion protein in mice is essentially harmless, no one can be sure what effect the same strategy would have in humans. Nevertheless, she said, "we conclude that the dramatic benefits to neuronal function and survival in prion-infected mice we have shown here support targeting neuronal prion protein directly as a therapeutic approach."
Mallucci and her colleagues, with collaborators at the University of Birmingham in the UK, report their findings in the February issue of Neuron, in a paper titled: "Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice."
vCJD is one of the transmissible spongiform encephalopathies (TSEs). As a result of abnormal folding, a normal cellular protein, called PrPc, becomes converted into a pathogenic form called PrP scrapie, or PrPSc. Once present, PrPSc can convert PrPc into more PrPSc.
In the UK, 158 people are thought to have died from vCJD since 1995, most probably as a result of eating meat contaminated with the agent that causes bovine spongiform encephalopathy (BSE).
Mallucci and her colleagues already found that early brain degeneration in prion-infected mice could be reversed if the neurons were depleted of prions. In their latest study they set out to discover whether the pathological changes they could see in those animals at the start of their earlier experiments were causing abnormal function, and whether that abnormal function recovered after the animals were "treated."
For the tests, they used mice that normally die from prion disease about 13 weeks after inoculation with prion protein, but which had been genetically manipulated to prevent their expressing PrPc from the age of 9 weeks.
Tests carried out on the mice included assessment of memory, presence of normal behaviors such as recognition of new objects and burrowing behavior, and neurophysiological tests of synaptic responses.
The researchers found that the animals with prion disease lost the ability to discriminate new objects and were less motivated to burrow than normal mice. Studies of the animals' brain tissue showed, likewise, a parallel impairment of signaling among brain cells, compared to normal mice.
Those deficits appeared early on in the disease, at about eight weeks after inoculation with prion protein.
When the animals' brains became depleted of prion protein, however, due to activation of the modified genes in their genomes, their memory and their burrowing behavior recovered, as did the signaling between their brain cells.
Writing in a preview in the same issue of Neuron, Howard Federoff and Timothy Mhyre of the University of Rochester School of Medicine and Dentistry in Rochester, N.Y., give reasons why the work by Mallucci and colleagues is important.
Those include the demonstration that there is a stage in the dysfunction caused by prion disease where it is reversible, and the fact that the work heralds a new era in therapeutics development for neurodegenerative diseases involving protein misfolding.