UCSF researchers have determined that two drugs currently approved to treat either malaria or certain psychotic illnesses are effective in treating mouse cells infected with the infectious protein known as the prion. Prions cause new variant Creutzfeldt-Jakob disease, the human equivalent of "mad cow disease," as well as numerous other rare neurodegenerative diseases in animals and humans.
Because the drugs have long been used, are known to cross the difficult-to-penetrate "blood-brain barrier," and caused a dramatic response in the cells, the UCSF researchers advocated the immediate establishment of clinical trials to investigate the efficacy of the drugs in patients dying of prion diseases. Prion diseases are relentless and uniformly fatal.
UCSF scientists have received federal approval to begin human trials of the two drugs for prion diseases. They confirmed yesterday that two patients suffering from Creutzfeldt-Jakob disease have been treated with one of the drugs under the "compassionate care" protocol.
The researchers report their findings in mouse cells and their recommendation for clinical trials in the August 14 issue of Proceedings of the National Academy of Science (PNAS).
"It's a big leap from findings in cell culture to those in humans, and we do not know if we will see a favorable response in humans. But the results we saw, in a cell model we consider valid, make this lead worth pursuing immediately," said the lead author of the study, Carsten Korth, MD. Korth is a postdoctoral scholar in the UCSF laboratory of senior author Stanley B. Prusiner, MD, UCSF professor of neurology and biochemistry and director of the UCSF Institute for Neurodegenerative Diseases. Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for discovering that a class of neurodegenerative diseases known as spongiform encephalopathies was caused by prions.
UCSF neurologists, in collaboration with the researchers, are in the final stages of developing the clinical trial to test the efficacy of the two drugs in the treatment of Creutzfeldt-Jakob disease (CJD) and other prion diseases. The drugs -- quinacrine and chlorpromazine - will be tested separately and in combination. The researchers hope to begin enrolling patients later this year.
The trial will be the first to test the effectiveness of drugs to treat human prion diseases, which can arise spontaneously, be inherited through a genetic mutation or develop through infectious transmission. (Infection can occur from ingestion of prion-contaminated meats, contamination through biological and pharmaceutical products and, as seen in the past, from cannibalism.)
While prion diseases have traditionally been rare in humans, they have provoked world attention in recent years as more than 105 teenagers and young adults in Europe are believed to have contracted new variant Creutzfeldt-Jakob disease (nvCJD) from eating beef from cattle with the bovine form of the condition. One in a million people each year develop a sporadic form of the condition, for which there is no known cause. Approximately 5-15% of all cases are inherited. Other infectious prion diseases include kuru, which arose among New Guinea natives.
The prion (PrPSC) is an infectious form of a normal protein, known as the cellular prion protein (PrPC), which exists in a healthy state in humans and many animals. The protein only becomes lethal when the tendril-like spirals that make up a portion of the protein molecule lose their normal conformation and flatten into so-called beta sheets. Once this process occurs, the misformed prion protein latches on to the spiral tendrils of other prion proteins and untwists them into flat sheets, like a wrestler pinning down an opponent.
The body probably regularly clears misfolded prion proteins from the brain's nerve cells. But when clearance doesn't occur, the deadly prion moves from one nerve cell to the next, relentlessly pinning and flattening other prion proteins as it goes. The accumulation of the flattened beta sheets within prion proteins leads to structural damage in the nerve cells that ultimately causes cell degeneration. This degeneration is seen in the tell-tale spongy appearance of affected brain tissue - thus the alternative name for prion diseases: transmissible spongiform encephalopathies.
While each prion strain contains a different protein conformation, each leads inexorably, if slowly, to dementia, paralysis and, ultimately, death.
A schematic of normal prion protein, as opposed to the infectious prion protein responsible for nvCJD and other prion diseases. The blue-green-grey coils at the top represent the alpha-helices found in both normal prion protein and the infectious form. The long red tail that hangs off the coils is also found in both forms of the protein, but researchers suspect that in the infectious form the tail folds up into flattened, so-called beta sheets.
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