The US National Institute of Allergy and Infectious Disease has awarded $20 million to a consortium of four institutions in the United States to further develop and test Proteome Systems' catalytic scavenger compounds as a potential treatment for radiation exposure caused by terrorist attacks or industrial accidents.
Proteome Systems' proprietary scavenger compounds were originally developed by Bedford, Mass.-based Eukarion, which was acquired by Proteome in December 2004. The compounds are called "scavengers" because they mop up excess free radicals, or superoxide, which can cause cell death, resulting in damage to internal organs such as the brain, the gastrointestinal tract, and the bone marrow.
Proteome Systems, which is part of the consortium, hopes to use the money to develop better scavenger compounds that persist longer in an organism's system. It will also try to develop compounds that can be administered orally, instead of by injection.
Based in North Ryde, Australia, and Woburn, Mass., Proteome Systems uses proteomic techniques to do biomarker and protein target discovery work that can lead to the development of diagnostics and therapeutics. The company teamed up with Eukarion in the late 1990's to investigate the effect of their scavenger compounds on the mitochondrial proteomes of mouse models.
Aside from Proteome Systems, other consortium members are The Medical College of Wisconsin, Henry Ford Health Systems in Detroit, and the University of Toronto. They will use Proteome Systems' scavenger compounds to study the effect of radiation on biological systems.
There is little to no commercialization potential for the systemic antioxidant drugs because commercial drug companies would not be interested in developing a drug that would only be used in the rare incident of an industrial accident, a terrorist attack, or a nuclear bomb.
Proteome Systems' catalytic scavenger compounds are small-molecule compounds that "show potential in a broad spectrum of therapeutic applications" in the neurodegenerative, cardiovascular, and inflammatory areas, said Steven Porges, CEO of Proteome Systems. "It is expected that these drugs will protect not only victims of exposure to a 'dirty bomb' or similar radioactive device, but also first responders who would need to go into attack areas."
The efficacy of Proteome Systems' scavenger compounds in protecting against free radicals was first shown in a paper published in 2004 in the Journal of Neurochemistry. The study showed that knockout mice that have an excess of mitochondrial superoxide could be rescued from neurodegeneration in their frontal cortex if they were injected with high doses of the antioxidant compounds. The compounds also partially alleviated physical problems in the mice, such as tremors, clumsiness, and seizures.
The study also compared the proteomes of mitrochondria from the brains of wild-type mice, knockout superoxide mice, and superoxide mice that were treated with the antioxidant compounds. Proteomic analysis showed that the proteins that were involved in oxidative stress were primarily components of the TCA cycle and the electron transport chain.
"[The study] was a pretty important first step to showing the real biological activity of these drugs in mammals," said Douglas Hinerfeld, the first author of the Journal of Neurochemistry paper who conducted the study at the Buck Institute (see Proteomics Pioneer).
To take the drugs forward so that they can eventually be used in humans, Proteome Systems will have to do clinical studies to show that the drugs have no toxic effects on humans, said Bob Bondaryk, vice president of business development at Proteome Systems. Because humans can not be dosed with radiation on purpose, efficacy studies for the drugs can only be done in animal models, he added.
Now that researchers have a "pretty good" handle on how the scavenger compounds intervene with oxidation, the new research using the NIAID funds will concentrate less on proteomics and more on classical medicinal chemistry, said Bondaryk.
The NIAID funding bid was organized by John Moulder, a cancer researcher and professor of radiation and oncology at the Medical College of Wisconsin, whose research has been devoted to developing methods for preventing and treating radiation injuries.
Bondaryk noted that there is little to no commercialization potential for the systemic antioxidant drugs because commercial drug companies would not be interested in developing a drug that would only be used in the rare incident of an industrial accident, a terrorist attack, or a nuclear bomb. However, there is still incentive for Proteome Systems and other companies to develop systemic antioxidant drugs because the US government will potentially buy and stockpile them.
"Ever since 9/11, there are laws on the books that require the US government to buy and stockpile these things," said Bondaryk. "There's a lot of money set aside specifically for this."
Aside from working on developing systemic drugs to treat radiation from industrial accidents or a terrorist attack, Proteome Systems is also currently working on developing topically applied drugs that can be used to protect skin against radiation burns that result from radiation treatment for cancer. The topically applied drugs use the same catalytic scavenger compounds as their active ingredient.
"One of the side effects of radiation therapy is dermatitis burns. Sometimes with head and neck cancer, the radiation burns out the mucus membrane so that it becomes painful to swallow," said Bondaryk. "What we're working on developing is an adjunct therapy for people who are trying to fight their cancers that could act as a cancer palliative that assuages pain."
Unlike systemic antioxidant drugs, the topically applied radiation therapy palliatives do have commercial appeal, Bondaryk noted.
Bondaryk added that Proteome Systems would also like to get back into some of the original proteomic work on aging that was being done at the Buck Institute prior to the Eukarion acquisition.
"We're probably going to advance some of the research in the neuro area with work on age-related memory loss," said Bondaryk.
— Tien-Shun Lee ([email protected])