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Adeno-associated viral vector mediated gene delivery of endothelin converting enzyme reduces Aβ deposits in APP+PS-1 transgenic mice


Year of Publication:
Contact PI Name:
David Morgan
Contact PI Affiliation:
Alzheimer's Research Laboratory Department of Molecular Pharmacology and Physiology School of Biomedical Sciences University of South Florida College of Medicine, Tampa, Florida, USA
N. Carty, K. Nash, D. Lee, M. Mercer, P.E. Gottschall, C. Meyers, N. Muzyczka, M.N. Gordon
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Study Goal and Principal Findings:

This study investigated effects of adeno-associated viral vector mediated gene delivery of endothelin converting enzyme on Aβ levels in APPxPS1 Tg mice. The overall accumulation of Aβ in the brain is attributed to an imbalance between its production and degradation/clearance. In recent years several endogenous proteases have been found which degrade Aβ in the brain and other tissues both in vivo and in vitro. Several current studies have implicated ECE as an important enzyme in the degradation of Aβ and preventing its accumulation. ECE inhibitor, phosphoramidon, caused a rapid accumulation of Aβ in a cell line expressing ECE but not in cells lacking ECE expression. Subsequent studies revealed that overexpression of ECE in cell lines reduced Aβ accumulation by approximately 90%. In vivo data from ECE (+/−) transgenic mice, which show 25% reductions in ECE-1 activity, also show significant increases in both Aβ40 and Aβ42 levels in the brain. Moreover, intraventricular injections of phosphoramidon, increase Aß in wild type and APP transgenic mice. This study investigated the effects of upregulating the ECE-1 enzyme by using a rAAV vector, serotype 5, on Aβ load in the brain. Immunohistochemistry for the haemagglutinin tag appended to ECE revealed strong expression in areas surrounding the injection sites but minimal expression in the contralateral regions. Immunohistochemistry for Aß decreased in the anterior cortex and hippocampus of mice receiving ECE cDNA. Further, decreases in Congo red positive deposits were also observed in both regions. These results indicate that increasing the expression of β amyloid degrading enzymes through gene therapy is a promising therapeutic avenue through which to treat AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Gene
Therapeutic Agent:
Endothelin Converting Enzyme (ECE-1)
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

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
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


Outcome Measured
Outcome Parameters
beta Amyloid Deposits
beta Amyloid Load
Dense-core/Compact Plaques
Endothelin Converting Enzyme 1 (ECE1)
Body Weight
Brain-Gross Morphometric Changes