About 60 researchers from 18 Canadian research institutions are in the process of establishing a research network to investigate three prion diseases in an effort to develop vaccines, diagnostics, and therapeutics for the fatal illnesses.
The researchers will use both proteomic and genomic techniques to try to find biomarkers for Bovine Spongiform Encephalopathy, or "mad cow" disease; Creutzfeldt-Jakob disease, the human form of mad cow disease; and Chronic Wasting Disease, a fatal prion disease present in captive and wild cervids, including deer and elk.
In addition, the scientists will study the epidemiology of the diseases both on a molecular and population level, the transmission of the diseases between species, and the risk factors for the diseases.
The research group, called PrioNet Canada, will be funded by CA$18.7 million ($14.9 million) from the Canadian Network Centers of Excellence, which is to be distributed over the next four years.
Around 20 principal investigators, as well as technicians, postdocs, graduate students, and summer students have signed on to the network so far.
Aside from linking up academic researchers, PrioNet Canada also hopes to foster collaborations between biotechnology and pharmaceutical companies that are working on prion diseases. Several Canadian and American companies have already agreed to commit matching funds for the organization, including Caprion Pharmaceuticals, Bioniche, Idexx Laboratories, Johnson and Johnson, and Amorfix Life Sciences.
"This is a huge opportunity," said Neil Cashman, the scientific director of PrioNet Canada. "The biggest challenge of establishing the network will be getting everyone to work on the same page."
Cashman, who is the Canadian Research Chair in Neurodegeneration and Protein Misfolding Diseases at the University of British Columbia, has been working on prions and prion diseases for nearly 20 years and spent the summer of 2004 criss-crossing Canada to convince various prion scientists to "throw their lots together" to join the new prion research network.
PrioNet Canada will have a matrix structure organization: One group of researchers will work on BSE, another group will work on CWD, and a third will work on CJD. To integrate three disease-theme groups, a number of "horizontal research program leaders" will work across diseases looking at prions in general.
"The matrix structure is kind of unwieldy when you first think about it, but it does promote the interaction of leadership from themes and scientific programs. People are forced to collaborate across diseases and programs. It's a big leadership, but it seems to be working," said Cashman.
Michael Coulthart (see Proteomics Pioneer), one of the PrioNet horizontal program leaders who founded Canada's first federal public health reference laboratory for human prion diseases in Winnepeg in 1998, will be working on a diagnostic for prion diseases using proteomic approaches. Researchers in his laboratory plan to use 2D gels and mass spectrometry to compare the proteomes of normal mice and mice that have been experimentally infected with BSE.
"One of the dominant thrusts for us will be to try to facilitate the application of useful biomarkers for CJD," said Coulthart. "The surveillance part of the reference laboratory really needs to be enhanced with technical approaches."
Coulthart's laboratory receives a few hundred human samples per year to be tested for CJD. About 30 cases per year are confirmed to be CJD, but so far, only one of those cases has been traced back to consumption of cattle infected with BSE. That individual had become infected while living abroad in the United Kingdom in the late 1980s and early 1990s, and became ill with vCJD in 2002.
"The vast bulk of CJD cases are not traceable to BSE at all," said Coulthart. "They're what's known as 'sporadic CJD.' It's a bit mysterious, but there are theories that the prion protein goes through a spontaneous post-translational misfolding event. If the misfolded proteins are not cleared through cell death, they begin to aggregate, and because they catalyze the misfolding of a common protein, there's a propagation effect."
For their part, Cashman and his team have been working on vaccine approaches to prion diseases. They expect to submit a paper in the fall describing some "encouraging preliminary data" about a vaccine that targets a unique epitope of a misfolded prion protein. Cashman's group originally discovered the epitope using immunoprecipitation, plate capture immunoassay, and flow cytometry techniques. The work was published in Nature Medicine in July 2003.
Other investigators are working on designing a vaccine for prion diseases by targeting the normal, cell-surface proteins that misfold when they come into contact with a disease-causing prion protein. However, that type of vaccine is unlikely to be effective, Cashman said, because animals have ubiquitous distribution of the targeted normal cell-surface proteins. A vaccine that induces antibodies against these ubiquitous proteins may cause autoimmunity.
"Unfortunately there's nothing that really works right now in terms of a vaccine or therapeutic [for prion diseases]," said Cashman.
The NCE originally put out a request for proposals for networks on BSE and other transmissible spongiform enchephalopathies in the spring of 2004. After speaking with the leading prion disease researchers in Canada, Cashman put together a letter of intent to the NCE and submitted it in February. It turned out that Cashman's LOI was the only one submitted for the prion NCE.
An international committee of reviewers reviewed Cashman's LOI and pointed out gaps that were missing in it. A full proposal for PrioNet is due in September. If the proposal is approved by the review committee, then PrioNet should be officially launched in November, Cashman said.
Though there have only been five cases of BSE in Canada since 1993, the effect of BSE on the Canadian economy has been tremendous, Cashman pointed out.
"The reason why the government got interested is that the economic hit from our few cases of BSE is between CA$6 billion and $CA 10 billion," Cashman said. "The borders with the US are still closed for cattle since the one case of BSE in Washington state in May 2003 that was traced back to Canada. The US accounted for the lion's share of our beef market."
— Tien-Shun Lee ([email protected])