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Active immunization against complement factor C5a: a new therapeutic approach for Alzheimer's disease

Bibliographic

Year of Publication:
2015
Contact PI Name:
Christine Landlinger
Contact PI Affiliation:
AFFiRiS AG, Vienna, Austria
Co-Authors:
Lisa Oberleitner, Petra Gruber, Birgit Noiges, Kristyna Yatsyk, Radmila Santic, Markus Mandler, Guenther Staffler
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

Inflammatory processes in AD are primarily triggered by the up-regulation of the complement system in response to misfolded and aggregated proteins or mislocalized nucleic acids and reactive microglia. Notably, the pro-inflammatory complement factor C5a and its receptor have been found to be up-regulated in microglia in the immediate surroundings of cerebral amyloid plaques in different mouse models of AD.  Previous studies found that the blockage of C5aR by the antagonist PMX205 lead to a therapeutic benefit in a rat model of neurodegeneration. This inhibitor was also tested in Tg2576 and 3xTg mice, two different mouse models of AD, and showed improved memory skills and reduced amyloid plaque formation.   In this study the authors tested the efficacy of active immunization with C5a-peptides  AFF1 and AFF2 in Tg2576 mice exhibiting either early or late stages of the AD-like disease. The authors observed that Tg2576 mice vaccinated at early stages of the disease showed significantly improved contextual memory accompanied by the reduction of microglia activation in the hippocampus and cerebral amyloid plaque load compared to control mice. Late-stage immunization also showed a decrease in the number of activated microglia, and improved memory function, however, had no influence on the amyloid β load. The authors speculate that active immunotherapy against complement factor C5a may be a new and effective approach for the treatment of AD-like disease

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
AFF1 Peptide
Therapeutic Target:
Complement C5a
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
AFF2 Peptide
Therapeutic Target:
Complement C5a

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
129S6

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Contextual Fear Conditioning
Histopathology
Activated Microglia
beta Amyloid Load
Immunology
Antibody Target Specificity
Antibody Titers
Pharmacodynamics
Target Engagement (Reduction Complement C5a-Plasma)
Toxicology
SHIRPA Test (General Health Muscle Function and Sensory Function)