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Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2008
Contact PI Name:
Ryuchi Morishita
Contact PI Affiliation:
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan
Co-Authors:
D. Takeuchi, N. Sato, M. Shimamura, H. Kurinami, S. Takeda, M. Shinohara, S. Suzuki, M. Kojima, T. Ogihara
Primary Reference (PubMED ID):
18288214
Funding Source:
Organization for Pharmaceutical Safety and Research of Japan
National Institute of Biomedical Innovation
Japanese Ministry of Public Health and Welfare
Takeda Science Foundation
Novartis Pharma AG
Chiyoda
Kanae Foundation
Japan Society for the Promotion of Sciences (JSPS)
Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
Study Goal and Principal Findings:

A new therapeutic approach to treat Alzheimer’s disease (AD) is needed, and the use of growth factors is considered to be a candidate. Hepatocyte growth factor (HGF) is a unique multifunctional growth factor, which has the potential effect to exert neurotrophic action and induce angiogenesis. In this study, we examined the effects of overexpression of human HGF plasmid DNA using ultrasound-mediated gene transfer into the brain in an Ab-infused cognitive dysfunction mouse model. We demonstrated that HGF gene transfer significantly alleviated Ab-induced cognitive impairment in mice in behavioral tests. These beneficial effects of HGF might be due to (1) significant recovery of the vessel density in the dentate gyrus of the hippocampus, (2) upregulation of BDNF, (3) a significant decrease in oxidative stress and (4) synaptic enhancement. A pharmacological approach including gene therapy to increase the HGF level in combination with anti-Aβ therapy might be a new therapeutic option for the treatment of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Gene
Therapeutic Agent:
Hepatocyte Growth Factor (HGF)
PubMed
ClinicalTrials
Patents
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Species:
Mouse
Model Type:
beta Amyloid Peptide Injection
Model Name:
ddY (beta Amyloid 1-40 Peptide Injection Model)
Strain/Genetic Background:
ddY

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
Drinking Behavior
Exploratory Activity
Operant Behavior Test
Spontaneous Alternation
Y Maze
Histopathology
Neuronal Loss
Biochemical
Brain-Derived Neurotrophic Factor (BDNF)
Brain-Derived Neurotrophic Factor (BDNF) mRNA
Hepatocyte Growth Factor (HGF)
Hepatocyte Growth Factor (HGF) mRNA
phospho-Protein Kinase B (phospho-Akt/PKB)
phospho-p38 Mitogen-Activated Protein Kinase (phospho-p38 MAPK)
Superoxide Anions (O2-)
Immunochemistry
Brain-beta Amyloid Deposits
Hepatocyte Growth Factor (HGF)
Superoxide Anions (O2-)
Synaptophysin
Microscopy
Capillary Network Quantification
Neuronal Loss
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