Vaccines for Neurodegenerative Diseases
Monday, March 24, 2008
Organizer: Michael Hagen, Wyeth Vaccines Research
Program
1:00-1:15
Welcome and Introduction
1:15-2:00
Development of the First DNA Epitope Vaccine for Alzheimer's Disease
David H. Cribbs, PhD; University of California, Irvine
2:00-2:45
Stable Aβ Trimers as Novel Alzheimer's Disease Vaccine Immunogens
Grant A. Krafft, PhD; Acumen Pharmaceuticals, Inc.
2:45-3:15
Break
3:15-4:00
Antibody Mediated Clearance of Amyloid Deposits and Restoration of Memory
Dave Morgan, PhD;University of South Florida
4:00-4:45
Aβ Immunization in Alzheimer's Disease Results in Plaque Removal but this may not be Sufficient to Halt the Progressive Dementia
James AR Nicoll, MD; University of Southampton
4:45-5:00
Closing Remarks
Abstracts
Development of the First DNA Epitope Vaccine for Alzheimer's Disease
David H. Cribbs, PhD
University of California, Irvine
The pioneering work by Dale Schenk and colleagues at Elan Pharmaceutical established that antibodies specific for the toxic amyloid-beta (Aβ) peptide could reduce the level of the peptide in the brains of transgenic mice that overexpress a human mutant form of the amyloid precursor protein. Unfortunately, the first immunotherapy clinical trial in Alzheimer's disease (AD) patients, the AN1792 vaccine, was halted during the Phase II stage due to meningoencephalitis in a subset of the patients that received the vaccine. Efforts to develop novel second-generation vaccines are now being pursued by various groups to eliminate or reduce the potential for adverse outcomes in patients. Our approach has focused of engineering a DNA epitope vaccine that includes a powerful synthetic T cell epitope, PADRE, in combination with the major amyloid-beta B cell epitope to promote a specific antibody response to amyloid-beta. To further amplify and direct the type of immune response to the DNA epitope vaccine we have incorporated a "molecular adjuvant", macrophage-derived chemokine (MDC/ CCL22), into the vaccine construct, which induced a Th2-mediated, anti-inflammatory cytokine response. In a pre-clinical study in 3xTg-AD mice we demonstrated that early immunizations induced a robust Th2 immune response that induced high titers of anti-Aβ antibody, which inhibited accumulation of Aβ pathology in aged animals. Importantly, DNA vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. Finally, a comparison of the differences in the immune response to vaccination with Aβ in several animal models and humans, as well as issues regarding efficacy and safety of immunotherapy will be presented.
Stable Aβ Trimers as Novel Alzheimer's Disease Vaccine Immunogens
Grant A. Krafft, PhD
Acumen Pharmaceuticals, Inc.
The Alzheimer's disease mechanistic landscape has changed dramatically over the past decade, as emerging studies now implicate amyloid β-derived diffusible ligands (ADDLs) as the likely cause of memory deficits in AD. ADDLs exert their disruptive effects by selectively activating specific post-synaptic receptors, and this leads to persistent compromise of long term potentiation and learning and memory. Based on this scenario, therapeutics designed to prevent ADDL formation or block ADDL activity should be highly effective in blocking AD onset and reversing AD memory deficits. This presentation will provide an overview of ADDL neurobiology and describe a novel AD vaccine approach based upon selective immune targeting of Aβ42 trimers, the likely intermediates on the assembly pathway from Aβ42 monomer to neurotoxic dodecameric A