 |
|
Metal-Protein Attenuation With Iodochlorhydroxyquin (Clioquinol) Targeting A Amyloid Deposition and Toxicity in Alzheimer Disease
A Pilot Phase 2 Clinical Trial
Craig W. Ritchie, MBChB, MRCPsych;
Ashley I. Bush, MBBS, PhD, FRANZCP;
Andrew Mackinnon, PhD;
Steve Macfarlane, MBBS;
Maree Mastwyk, BN;
Lachlan MacGregor, MBBS;
Lyn Kiers, MBBS, FRACP;
Robert Cherny, PhD;
Qiao-Xin Li, PhD;
Amanda Tammer, PhD;
Darryl Carrington, BSc;
Christine Mavros, BSc;
Irene Volitakis, BSc;
Michel Xilinas, MD, DSc;
David Ames, MD;
Stephen Davis, MD, FRACP;
Konrad Beyreuther, PhD;
Rudolph E. Tanzi, PhD;
Colin L. Masters, MD
Arch Neurol. 2003;60:1685-1691.
Background Alzheimer disease (AD) may be caused by the toxic accumulation of  -amyloid (A).
Objective To test this theory, we developed a clinical intervention using clioquinol, a metal-protein–attenuating compound (MPAC) that inhibits zinc and copper ions from binding to A, thereby promoting A dissolution and diminishing its toxic properties.
Methods A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease.
Results Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale,  25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma A42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated.
Conclusion Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein–attenuating compound.
From the Departments of Pathology (Drs Ritchie, Bush, Macfarlane, Cherny, Li, Tammer, and Masters; Mss Mastwyk, Mavros, and Volitakis; and Mr Carrington), Medicine (Drs MacGregor, Kiers, and Davis), and Psychiatry (Dr Ames), The University of Melbourne, The Mental Health Research Institute of Victoria, Parkville, Victoria (Drs Ritchie, Bush, Mackinnon, Macfarlane, Cherny, Li, Tammer, and Masters; Mss Mastwyk, Mavros, and Volitakis; and Mr Carrington); the Department of Psychiatry and Behavioural Science, Royal Free Campus, University College London, London, England (Dr Ritchie); the Department of Psychological Medicine, Monash University, Clayton, Victoria (Dr Mackinnon); the Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria (Drs MacGregor, Kiers, and Davis); the Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden (Dr Xilinas); the Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Genetics and Aging Research Unit, Massachusetts General Hospital, Boston (Drs Bush and Tanzi). Dr Ritchie has been paid for his time and effort in analyzing the results from the trial sponsor, Prana Biotechnology. Drs Bush and Tanzi are paid consultants, are on the Scientific Advisory Committee, and are stockholders of Prana Biotechnology and had no input into the drafting or review of any portion of the manuscript other than those portions pertaining to study concept and design and consultation on biochemistry and no input into the analysis of the data from the other portions. Drs Macfarlane and MacGregor and Ms Mastwyk were employed by the Mental Health Research Institute through funds provided by Prana Biotechnology. Dr Cherny is a stockholder in Prana Biotechnology. Dr Xilinas has financial and intellectual interests in the development of clioquinol. Dr Beyreuther is on the Scientific Advisory Committee of Prana Biotechnology. Dr Masters is a director of Prana Biotechnology, chairperson of its Scientific Advisory Committee, and a stockholder.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED ARTICLE
Metal Chelation Therapy for Alzheimer Disease
Roger N. Rosenberg
Arch Neurol. 2003;60(12):1678-1679.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Iron accumulation in syndromes of neurodegeneration with brain iron accumulation 1 and 2: causative or consequential?
Schneider et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:589-590.
FULL TEXT
Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+
Andersson et al.
Proc. Natl. Acad. Sci. USA 2009;106:8374-8379.
ABSTRACT
| FULL TEXT
Radiation Dosimetry of {beta}-Amyloid Tracers 11C-PiB and 18F-BAY94-9172
O'Keefe et al.
JNM 2009;50:309-315.
ABSTRACT
| FULL TEXT
Increasing Cu bioavailability inhibits A{beta} oligomers and tau phosphorylation
Crouch et al.
Proc. Natl. Acad. Sci. USA 2009;106:381-386.
ABSTRACT
| FULL TEXT
Longitudinal prognostic value of serum "free" copper in patients with Alzheimer disease
Squitti et al.
Neurology 2009;72:50-55.
ABSTRACT
| FULL TEXT
Sequestration of Copper from {beta}-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents
Wu et al.
J. Biol. Chem. 2008;283:31657-31664.
ABSTRACT
| FULL TEXT
Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators
Amit et al.
FASEB J. 2008;22:1296-1305.
ABSTRACT
| FULL TEXT
Insights into Zn2+ homeostasis in neurons from experimental and modeling studies
Colvin et al.
Am. J. Physiol. Cell Physiol. 2008;294:C726-C742.
ABSTRACT
| FULL TEXT
Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-{beta} Peptide
Donnelly et al.
J. Biol. Chem. 2008;283:4568-4577.
ABSTRACT
| FULL TEXT
Clioquinol Promotes Cancer Cell Toxicity through Tumor Necrosis Factor {alpha} Release from Macrophages
Du et al.
J. Pharmacol. Exp. Ther. 2008;324:360-367.
ABSTRACT
| FULL TEXT
Disease-modifying therapies for Alzheimer disease: Challenges to early intervention
Cummings et al.
Neurology 2007;69:1622-1634.
ABSTRACT
| FULL TEXT
In Vitro Characterization of Pittsburgh Compound-B Binding to Lewy Bodies
Fodero-Tavoletti et al.
J. Neurosci. 2007;27:10365-10371.
ABSTRACT
| FULL TEXT
Clioquinol, a Therapeutic Agent for Alzheimer's Disease, Has Proteasome-Inhibitory, Androgen Receptor-Suppressing, Apoptosis-Inducing, and Antitumor Activities in Human Prostate Cancer Cells and Xenografts
Chen et al.
Cancer Res. 2007;67:1636-1644.
ABSTRACT
| FULL TEXT
Subunit-specific modulation of T-type calcium channels by zinc
Traboulsie et al.
J. Physiol. 2007;578:159-171.
ABSTRACT
| FULL TEXT
Clioquinol, a Cu(II)/Zn(II) Chelator, Inhibits Both Ubiquitination and Asparagine Hydroxylation of Hypoxia-inducible Factor-1{alpha}, Leading to Expression of Vascular Endothelial Growth Factor and Erythropoietin in Normoxic Cells
Choi et al.
J. Biol. Chem. 2006;281:34056-34063.
ABSTRACT
| FULL TEXT
Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the A{beta} amyloid pathway
Masters and Beyreuther
Brain 2006;129:2823-2839.
ABSTRACT
| FULL TEXT
Elevated cortical zinc in Alzheimer disease.
Religa et al.
Neurology 2006;67:69-75.
ABSTRACT
| FULL TEXT
Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF {beta}-amyloid, and h-tau.
Squitti et al.
Neurology 2006;67:76-82.
ABSTRACT
| FULL TEXT
Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells.
Ding et al.
Molecular Cancer Therapeutics 2006;5:1864-1872.
ABSTRACT
| FULL TEXT
Degradation of the Alzheimer Disease Amyloid beta-Peptide by Metal-dependent Up-regulation of Metalloprotease Activity
White et al.
J. Biol. Chem. 2006;281:17670-17680.
ABSTRACT
| FULL TEXT
Copper-mediated Amyloid-beta Toxicity Is Associated with an Intermolecular Histidine Bridge
Smith et al.
J. Biol. Chem. 2006;281:15145-15154.
ABSTRACT
| FULL TEXT
Excess of serum copper not related to ceruloplasmin in Alzheimer disease
Brenner et al.
Neurology 2006;66:294-295.
FULL TEXT
Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition: A TARGET FOR NEUROPROTECTION IN THE CENTRAL NERVOUS SYSTEM
Siddiq et al.
J. Biol. Chem. 2005;280:41732-41743.
ABSTRACT
| FULL TEXT
Translational Research on the Way to Effective Therapy for Alzheimer Disease
Rosenberg
Arch Gen Psychiatry 2005;62:1186-1192.
ABSTRACT
| FULL TEXT
Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model
Nguyen et al.
Proc. Natl. Acad. Sci. USA 2005;102:11840-11845.
ABSTRACT
| FULL TEXT
Perinatal {omega}-3 polyunsaturated fatty acid supply modifies brain zinc homeostasis during adulthood
Jayasooriya et al.
Proc. Natl. Acad. Sci. USA 2005;102:7133-7138.
ABSTRACT
| FULL TEXT
Metal Ion-dependent Effects of Clioquinol on the Fibril Growth of an Amyloid {beta} Peptide
Raman et al.
J. Biol. Chem. 2005;280:16157-16162.
ABSTRACT
| FULL TEXT
Anticancer Activity of the Antibiotic Clioquinol
Ding et al.
Cancer Res. 2005;65:3389-3395.
ABSTRACT
| FULL TEXT
Methylation of the Imidazole Side Chains of the Alzheimer Disease Amyloid-{beta} Peptide Results in Abolition of Superoxide Dismutase-like Structures and Inhibition of Neurotoxicity
Tickler et al.
J. Biol. Chem. 2005;280:13355-13363.
ABSTRACT
| FULL TEXT
SMON, clioquinol, and copper
Kumar and Knopman
Postgrad. Med. J. 2005;81:227-227.
FULL TEXT
Curcumin Inhibits Formation of Amyloid {beta} Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo
Yang et al.
J. Biol. Chem. 2005;280:5892-5901.
ABSTRACT
| FULL TEXT
Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease
Treiber et al.
J. Biol. Chem. 2004;279:51958-51964.
ABSTRACT
| FULL TEXT
Alzheimer's Disease
Cummings
NEJM 2004;351:56-67.
FULL TEXT
Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-{beta} Precursor Protein Gene
Bellingham et al.
J. Biol. Chem. 2004;279:20378-20386.
ABSTRACT
| FULL TEXT
Serum Copper: A Biomarker for Alzheimer Disease?
Bush and Strozyk
Arch Neurol 2004;61:631-632.
FULL TEXT
Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links {beta}-Amyloid (A{beta}) and Generates A{beta}-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease
Nagano et al.
J. Biol. Chem. 2004;279:14673-14678.
ABSTRACT
| FULL TEXT
Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease
Friedlich et al.
J. Neurosci. 2004;24:3453-3459.
ABSTRACT
| FULL TEXT
Compound May Be Effective In Reducing Alzheimer's Plaques
Moran
Psychiatr. News 2004;39:23-23.
FULL TEXT
Metal Chelation Therapy for Alzheimer Disease
Rosenberg
Arch Neurol 2003;60:1678-1679.
FULL TEXT
|
