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Established Malaria Drug Being Tested against Prions, CJD Disease

Based on effectiveness in treating prion-infected mouse cells, researchers at the University of California, San Francisco (UCSF) will be conducting limited clinical tests with an antimalarial drug and an antipsychotic drug to determine whether such treatments can forestall progress of new variant Creutzfeldt-Jakob disease (nvCJD). Both drugs contain tricyclic structures with aliphatic chains that are capable of traversing the blood-brain barrier (BBB), a key trait for any drug that will be used in treating patients with this disease, which affects the central nervous system (CNS).

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The rapidly deadly disease of nvCJD arises among humans who consume or otherwise contact meat or other contaminated tissues from cattle with bovine spongiform encephalopathy (BSE), the disease that is more widely known as mad cow disease. The unusual infectious agents known as prions are considered responsible for causing these and other degenerative neurological diseases, known as transmissible spongiform encephalopathies (TSEs), which also include scrapie in sheep. At least in humans, additional, more slowly acting forms of CJD either may be inherited or arise spontaneously. (See previous ASM News articles on TSEs in June 2001, p. 295, February 2001, p. 64, and August 2000.)

In their search for compounds to treat these diseases, UCSF researchers led by Carsten Korth and Stanley Prusiner have used scrapie-infected neuroblastoma cells from mice to screen drug candidates. One early, seeming success in these tests included several anticholesterol statin drugs. However, although effective in vitro, they were later rejected because they would be needed at levels that would have too-severely depleted cholesterol in the body.

On another tack, the researchers began screening a slew of compounds that cross the BBB, a strategy that led them to one family of drugs with tricyclic structures, some of which have been used for nearly 50 years to treat psychoses. One of those drugs that proved effective in the in vitro cell assay is chlorpromazine. Moreover, identifying it shortly led to the antimalarial drug, quinacrine, the "structural antecedent of the phenothiazines," the class to which chlorpromazine belongs, according to Korth, Prusiner, and their other collaborators at UCSF, who report their mouse cell culture findings in the 14 August 2001, issue of the Proceedings of the National Academy of Sciences (98:9836-9841).

In these tests, quinacrine proves 10 times more potent than chlorpromazine, according to the UCSF team. That potency difference led them to produce and test a variety of quinacrine derivatives, but the potencies of those proved more or less similar to that of chlorpromazine, "emphasizing the importance of the aliphatic side chain," they note. These "findings define a new class of antiprion compounds consisting of a tricyclic scaffold with an aliphatic side chain extending from the middle ring moiety."

With these robust test results in hand and knowing that nvCJD patients face a rapid decline to dementia and death, the UCSF researchers sought permission from officials at the Food and Drug Administration (FDA) to move quickly into clinical trials with quinacrine and chlorpromazine, both of which long ago passed safety tests and were approved for their respective antimalarial and antipsychotic clinical uses. Already at least two patients are receiving treatment under the agency's compassionate use protocol, and additional patients will be enrolled soon, the researchers say. "The drugs...will be tested separately and in combination."

In a related development, Prusiner and David Peretz at UCSF and their collaborators at the Scripps Research Institute in La Jolla, Calif., and at the University of Oxford in Oxford, England, report that antibodies can inhibit prion propagation in cultured mouse cells and also can clear prions from cells. Their experiments "indicate that specific antibodies may become a powerful weapon in the fight against neurodegenerative diseases associated with the accumulation of misfolded proteins," the researchers report in the 16 August 2001 issue of Nature (412:739-743).

Jeffrey L. Fox