CLINICAL STUDY FOR THE TREATMENT OF HUMAN PRION DISEASES

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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 priori 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.