Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid depositing transgenic mice



Year of Publication:
Contact PI Name:
David Morgan
Contact PI Affiliation:
Department of Molecular Pharmacology and Physiology, Byrd Alzheimer Institute, University of South Florida, Tampa, Florida, USA
Lori Lebson, Kevin Nash, Siddharth Kamath, Donna Herber, Nikisha Carty, Daniel Lee, Qingyou Li, Karoly Szekeres, Umesh Jinwal, John Koren, Chad A. Dickey, Paul Gottschall, Marcia N. Gordon
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Johnnie B. Byrd Alzheimer’s Center and Research Institute
Alzheimer's Association
Study Goal and Principal Findings:

A major question for gene therapy in brain concerns methods to administer therapeutic genes in a uniform manner over major portions of the brain. A second question in neuroimmunology concerns the extent to which monocytes migrate to the CNS in degenerative disorders. Here we show that CD11b+ cells (largely monocytes) isolated from the bone marrow of green fluorescent protein (GFP) expressing donors spontaneously home to compacted amyloid plaques in the brain. Injections of these cells as a single pulse show a rapid clearance from circulation (90 minute half-life) and tissue residence half-lives of roughly 3 days. The uptake into brain was minimal in nontransgenic mice. In transgenic mice containing amyloid deposits, uptake was dramatically increased and associated with a corresponding decrease in monocyte uptake into peripheral organs compared to nontransgenic littermates. Twice weekly infusions of the CD11b+ bone marrow cells transfected with a genetically engineered form of the protease neprilysin completely arrest amyloid deposition in an aggressively depositing transgenic model. Exploiting the natural homing properties of peripherally derived blood cells to deliver therapeutic genes has the advantages of access to the entire CNS, expression largely restricted to sites of injury, low risk of immune reactivity, and fading of expression if adverse reactions are encountered. These observations support the feasibility of testing autologous monocytes for application of therapeutic genes in human CNS disease. Moreover, these data support the results from bone marrow grafts that circulating CD11b+ cells can enter the CNS without requiring the use of lethal irradiation.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Cell-based
Therapeutic Agent:
CD11b+ Cells
Therapeutic Target:
Multi Target

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
Congophillic Amyloid Deposits
Dense-core/Compact Plaques
Brain-beta Amyloid Deposits
Brain-beta Amyloid Peptides
Activated Microglia
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Cell Biology
Cell Viability
Gene Delivery to Brain

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