title: A preclinical assessment of neural stem cells as delivery vehicles for anti-amyloid therapeutics.
abstract: Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America.
authors.forename: eMalick G
authors.initials: eG
authors.lastname: Njie
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kantorovich
authors.forename: Garrett W
authors.initials: GW
authors.lastname: Astary
authors.forename: Cameron
authors.initials: C
authors.lastname: Green
authors.forename: Tong
authors.initials: T
authors.lastname: Zheng
authors.forename: Susan L
authors.initials: SL
authors.lastname: Semple-Rowland
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Steindler
authors.forename: Malisa
authors.initials: M
authors.lastname: Sarntinoranont
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Streit
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D016086:Lentivirus / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation*; D058225:Plaque, Amyloid / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D020780:Matrix Metalloproteinase 9