LAVAL, Quebec—As part of a larger program to develop antivirals, scientists at REPLICor and Hamilton, Mont.-based NIAID Rocky Mountain Laboratories collaborated on the development and characterization of a therapeutic that may help fight human and animal prion disorders, including scrapie, bovine spongiform encephalopathy (BSE or mad cow) and Creutzfeld-Jakob disease (CJD). They recently described their efforts in the journal Antimicrobial Agents and Chemotherapy.
For REPLICor, the research is just part of its larger effort to develop therapeutics against infectious diseases, a program that centers on the lead compound REP 9, which has shown activity against both prion disorders and viral infections.
While not widely prevalent in the human population, prion disorders have garnered increased attention in recent years as the prevalence of BSE has increased in global cattle populations. The U.S.D.A. pegged the U.S. beef market at $78-billion in 2005, which provides a significant incentive to develop new therapeutics that will avoid the devastation experienced by the United Kingdom in the late 1980s and early 1990s.
According to Dr. Byron Caughey, senior investigator at the Rocky Mountain Labs, there have been tangible experimental advances for prion diseases, but none of the treatments have shown clear efficacy. "In experimental settings, a number of compounds and immunotherapies can dramatically prolong the survival times of TSE-infected rodents when administered prophylactically," he says "A few compounds also have been shown to be helpful in the face of established brain infections in the laboratory."
Knowing that prion disorders are triggered when natural proteins in the body change shape and aggregate to form tangles, the REPLICor scientists looked to prevent or disrupt this aggregation process using modified oligonucleotides. In particular, they chose phosphorothioated (PS-) oligonucleotides, which they hoped would bind more tightly to the prion proteins. They then enlisted the help of NIAID to test the resulting compounds.
"Since we are developing broad-spectrum drugs, it is essential that we collaborate with experts in each disease," says Dr. Jean-Marc Juteau, senior scientist and co-founder of REPLICor. "It would be nearly impossible to test in house all the viruses, prion and other infectious agents."
Using a mouse model of scrapie, a prion disease of sheep, researchers found that the PS-oligonucleotides prevented aggregation as well as breakdown pre-existing aggregates. "The drug could probably be of utility as a treatment to control the disease," Juteau says. "But we can also foresee the potential market of blood product and tissue treatment for inhibition of transmission of prion diseases."
And because the PS-oligonucleotides have a simple chemistry and work by preventing protein aggregation, their therapeutic indications may extend beyond prion diseases. Says Caughey: "It is possible that by a similar mechanism, these compounds could reduce the formation of the abnormal protein aggregates that appear to cause a number of other diseases such as Alzheimer's, Parkinson's and Huntington's."
According to Juteau, REPLICor already has data showing the compounds have strong anti-malarial potential, and the company expects to file INDs in late 2006 or early 2007 for the treatment of hepatitis C and influenza.
In the meantime, the scientists acknowledge that there is still a long way to go before getting these compounds into the clinic as prion therapeutics. "We want to further resolve the mode of action in prions in order to improve the activity," Juteau says, but the company does foresee drug formulations that are active against both viral infections and prion diseases.
