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Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice

Bibliographic

Year of Publication:
2006
Contact PI Name:
Todd E. Golde
Contact PI Affiliation:
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida, USA
Co-Authors:
Yona Levites, Karen Jansen, Lisa A. Smithson, Rachel Dakin, Vallie M. Holloway, Pritam Das
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Study Goal and Principal Findings:

Accumulation of amyloid β protein (Aβ) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer’s disease (AD). Active or passive immunizations targeting Aβ are therefore of great interest as potential therapeutic strategies. This study evaluated the use of recombinant anti-Aβ single-chain variable fragments (scFvs) as a potentially safer form of anti-Aβ immunotherapy. They have generated and characterized three anti-Aβ scFvs that recognize Aβ1–16, Aβx-40, or Aβx-42. To achieve widespread brain delivery, constructs expressing these anti-Aβ scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Aβ scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Aβ deposition by 25–50%. These data suggest that intracranial anti-Aβ scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a “somatic brain transgenic” paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
AAV1 Encoding anti-Aβ40 Specific Single Chain Variable Fragments (scFvs)
Therapeutic Target:
beta Amyloid Peptide
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
AAV1 Encoding anti-Aβ42 Specific Single Chain Variable Fragments (scFvs)
Therapeutic Target:
beta Amyloid Peptide
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
AAV1 Encoding anti-pan Aβ Single Chain Variable Fragments (scFvs)
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
B6C3F1/Tac
Species:
Mouse
Model Type:
APP
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
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
Histopathology
beta Amyloid Deposits
Fibrillar Plaques
Biochemical
Brain-Formic Acid Soluble beta Amyloid Peptides
Brain-Buffer Soluble beta Amyloid Peptides
Immunochemistry
Brain-beta Amyloid Deposits
Biomarker
Plasma-Complex of Antibody and beta Amyloid
Immunology
Antibody Target Specificity
Antibody Characterization
Pharmacokinetics
Antibody Concentration-Brain
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)