Immunotherapy for Neurodegenerative Diseases
Tuesday, March 27, 2007
Presented By
Presented by Biochemical Pharmacology Discussion Group and American Chemical Society's New York Section
Organizers: Robert Martone, Wyeth; David D. Auperin, Pfizer
Program:
1:00 PM
Welcome and Introduction
1:10 PM
Soluble AB Oligomers as the 'Smoking Gun' in Alzheimer's Disease Neutralization by Immunotherapy
Dennis Selkoe, MD
Harvard Medical School and Brigham and Women's Hospital.
2:00 PM
Targeting Prions with Immunotherapy
Thomas Wisniewski, MD
New York University School of Medicine
2:50 PM
Refreshments
3:15 PM
a-Synuclein Clearance and Immunotherapy Strategies in the Development of New Treatments for Lewy Body Dementia and Parkinson's Disease
Eliezer Masliah, MD
University of California, San Diego.
4:05 PM
Engineered Antibody Fragments as Potential Huntington's and Parkinson's Disease Therapeutics
Anne Messer, PhD
New York State Department of Health
4:55 PM
Closing
Abstracts
Soluble Aβ Oligomers as the "Smoking Gun" in Alzheimer's Disease: Neutralization by Immunotherapy
Dennis J. Selkoe, MD
Harvard Medical School and Brigham and Women's Hospital
Evidence from many laboratories continues to support the hypothesis that an imbalance between the production and clearance of the amyloid β-protein (Aβ) is fundamental to the pathogenesis of all forms of Alzheimer's disease. Our laboratory has approached this hypothesis by designing experiments to address the three principal arms of the life cycle of Aβ: production, degradation and aggregation. Regarding production, we identified presenilin as β-secretase, an unprecedented intramembrane aspartyl protease. Regarding Aβ degradation, we have obtained evidence that genetic up- or down-regulation of known Aβ-degrading proteases substantially alters Aβ burden and associated cytopathology in mice. In the area of Aβ aggregation, we have observed that naturally-secreted, soluble oligomers of human Aβ, particularly trimers. are potent inhibitors of hippocampal long term potentiation and that their effects can be abrogated by Aβ antibodies either produced endogenously or administered exogenously. Taken together, our data point to several distinct strategies, including immunotherapy, for downregulating cerebral Aβ levels to prevent Alzheimer's disease.
Targeting Prions with Immunotherapy
Thomas Wisniewski, MD
New York University
Prion disease are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of a normal, self protein call PrPC (C for cellular) to a pathological and infectious conformation known as PrPSc (Sc for scrapie). Currently all prion disease are without effective treatment and are universally fatal. The emergence of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease has highlighted the need to develop possible therapies. In Alzheimer's disease (AD), which has similarities to prion disease, both passive and active immunization has been shown to be highly effective in model animals at preventing disease and cognitive deficits. In a human trial of active vaccination in AD despite indications of cognitive benefits in patient with an adequate humoral response, 6% of patients developed significant complications related to excessive cell-mediated immunity. This experience highlights the need with immunotherapy design directed against a self-antigen to finely balance an effective humoral immune response with potential auto-immune toxicity. Many prion disease have the gut as a porta