Targeting widespread sites of damage in dystrophic muscle: engrafted macrophages as potential shuttles.
Inherited muscle diseases are characterized by widespread muscle damage in the body. This limits the clinical relevance of cell or gene therapy based upon direct injections into muscles. One way to circumvent this obstacle would be to use circulating cells, capable of homing naturally to the sites of lesion, to deliver therapeutic substances. Certain muscular dystrophies present successive cycles of degeneration-regeneration. These sporadic necrotic lesions trigger local inflammations with subsequent infiltration of blood-borne mononuclear cells. We have, therefore, tested the possibility that homing monocytes and macrophages could be appropriate shuttles for delivering a therapeutic agent to disseminated pathogenic sites, their targeting being triggered by the pathogeny itself. First, fluorescently labeled immortalized monocytes were intravenously injected into mice which had previously undergone freeze-damaging of individual muscles. In agreement with our hypothesis, intense labelling was observed in the muscle, specifically in damaged regions. Second, the technique was adapted to meet the needs of chronic diseases with characteristic continuous, widespread degeneration of muscle fibers, by creating a reservoir of genetically engineered monocytes, via bone marrow transplantation. Mdx mice received bone marrow from transgenic mice expressing the lacZ reporter gene, under the control of the vimentin promoter, which is active in monocytes and macrophages. Histological and molecular analyses demonstrated the homing of engineered macrophages at the sites of muscle damage, for periods as long as 2 months. Bone marrow progenitor cells, appropriately engineered to elicit the synthesis, in macrophages, of therapeutically relevant substances, may be of clinical value in various pathologies involving an inflammatory phase.
Parrish
E P
EP
Neuroplasticite et Therapeutique, INSERM U421, Faculte de Medicine, France.
Cifuentes-Diaz
C
C
Li
Z L
ZL
Vicart
P
P
Paulin
D
D
Dreyfus
P A
PA
Peschanski
M
M
Harris
A J
AJ
Garcia
L
L
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D002460:Cell Line; D017690:Cell Transplantation; D017931:DNA Primers; D004195:Disease Models, Animal; D005240:Feasibility Studies; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009132:Muscles / Q000276:immunology* / Q000473:pathology; D009136:Muscular Dystrophies / Q000276:immunology* / Q000473:pathology / Q000628:therapy
D017931:DNA Primers