Prion diseases are neurodegenerative diseases of humans and animals, which are invariably fatal and lead to death within a year after the onset of clinical symptoms. As with most other neurodegenerative diseases, no effective therapy is known. Treatment of patients with sporadic (s) Creutzfeldt-Jakob disease (CJD), the most common human prion disease, employing quinacrine will be studied. CJD patients will initially receive a racemic mixture of quinacrine. Quinacrine has been shown to inhibit prion formation in cultured ScN2a cells at submicromolar concentrations. Additionally, experimental prion disease in mice will be treated with quinacrine. In studies with ScN2a cells, the (S)-quinacrine isomer was 2 to 3 times more potent with respect to inhibiting prion formation than (R)-quinacrine; these isomers will be compared to the racemic mixture in mice. Concurrently, murine models will be used to evaluate treatment of prion disease with new drugs produced through empirical and rational drug design. The empirical drug program will utilize a combinatorial chemistry approach with quinacrine as the lead compound. Quinacrine will be modified and tested in the ScN2a cell culture system. We plan to test about 2000 new quinacrine analogs per year. Only compounds that are 10 times more potent than quinacrine with respect to antiprion activity will be evaluated in mice. Initially, these new antiprion compounds will be screened for toxicity. Compounds that are determined to be sufficiently nontoxic will then be tested for their ability to block prion synthesis in transgenic (Tg) mice. Besides empirical drug discovery, we plan to expand a rational drug design program along two lines of investigation. Attempts will be made to increase the potency of quinacrine by further modifying the aliphatic side chain. Recent studies have shown that bis-quinacrine analogs are more potent than quinacrine by a factor of ten. We also plan to dissect the mode of quinacrine action through studies of PrP trafficking in cultured cells. A second line of rational drug design involves modifying compound 60, which was found by mimicking dominant negative inhibition of prion synthesis. In order to understand dominant negative inhibition of prion synthesis, the structures of dominant negative PrPs will be determined using NMR spectroscopy. The information obtained from these dominant negatives should facilitate improvements in the design of existing drugs or lead to the production of new drugs. PRINCIPAL INVESTIGATOR The PI of this PPG, Dr. Stanley Prusiner, is a professor of Biochemistry and the director of Neurodegenerative diseases at UCSF. He has extensive experience in the area of virology and neurology and in directing research projects of this magnitude. He is a leading authority in prion research for the last several years. He is the recipient of numerous national and international awards, including the nobel prize in 1998. He has published more than 200 articles in scientific journals of interanational repute. He has trained and supervised several researchers/clinicians and thus is well qualified to lead this group and the project. REVIEW OF INDIVIDUAL COMPONENTS PROJECT 1: Clinical Study of Quinacrine for Treatment of Human Prion Diseases; Dr. Richard Miller (PL) DESCRIPTION (provided by applicant): Creutzfeldt-Jakob disease (CJD)is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Moreover, an epidemic of new variant CJD (nvCJD) in England has raised serious concerns regarding the safety of the world's beef supply; the possibility that prions might be passed through the blood has led to the banning of blood or tissue donations from individuals who have resided in England. The discovery of an effective therapy for prion diseases would have enormous human and economic implications. Recent results from experiments in Dr. Prusiner's laboratory show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal prion proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD. We propose a treatment study for patients with sporadic CJD (sCJD) with racemic quinacrine. Over three years, 90 patients will be admitted to the University of California at San Francisco (UCSF) NIH-funded clinical research center where a diagnosis of sCJD will be determined and where patients will enter into a randomized, double-blinded, treatment study with quinacrine. Patients will be divided into two quinacrine arms, a high-dose titration (450 mg daily) and a low-dose titration (75 mg daily). They will be treated for one year and then be followed through to the end of the five-year study period. The dose of quinacrine may be increased or decreased in each patient depending on clinical deterioration or toxicity, respectively. Survival will be the primary outcome measure of this clinical study. Also, additional outcome measures will be used that assess activities of daily living, cognition, MRI and EEG. We hypothesize that patients in the high-dose quinacrine arm will have increased survival and a slower rate of neurological progression compared with patients in the low dose arm. By year four of this program Project grant (PPG), we hope to begin a clinical study with a new compound, developed in other Projects in this PPG that shows even greater efficacy than racemic quinacrine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG021601-03
Application #
6921298
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O1))
Program Officer
Monjan, Andrew A
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-15
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$4,792,766
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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