Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice.
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 GFP (green fluorescent protein)-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 min half-life) and tissue residence half-lives of approximately 3 d. 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.
Lebson
Lori
L
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida 33612, USA.
Nash
Kevin
K
Kamath
Siddharth
S
Herber
Donna
D
Carty
Nikisha
N
Lee
Daniel C
DC
Li
Qingyou
Q
Szekeres
Karoly
K
Jinwal
Umesh
U
Koren
John
J
Dickey
Chad A
CA
Gottschall
Paul E
PE
Morgan
Dave
D
Gordon
Marcia N
MN
D000074183:ATPases Associated with Diverse Cellular Activities; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology* / Q000628:therapy*; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000201:enzymology; D039481:CD11b Antigen / Q000008:administration & dosage*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000032:analysis; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000637:transplantation*; D015260:Neprilysin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D000682:Amyloid; D015415:Biomarkers; D039481:CD11b Antigen; C485191:GFP10 Protein; C491455:Psmc5 protein, mouse; D049452:Green Fluorescent Proteins; D015260:Neprilysin; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities