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.

Stem cells as a promising therapeutic approach for Alzheimer’s disease: a review

“…Novel neurons, derived from donor cells or activated neurogenesis, demonstrated their ability to mediate structural and functional integration in the pre-existing network and to modulate neurogenesis (Yu et al 2013a(Yu et al , 2013bBonaguidi et al 2011). These new neurons are capable of secreting neurotrophic factors (Enciu et al 2011) and increasing brain ACh levels, thus improving neurocognitive functions in AD animal models (Park et al 2013;Park et al 2012;Yang et al 2013;Ma et al 2013;Njie et al 2012). Furthermore, genetically reprogrammed stem cells can possess the migratory capacity and can be employed as vehicles to deliver neurotrophic factors or to enhance genetic expression that can alter the AD pathway (Mucke 2009).…”

Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases

“…The greatest engraftment in mouse brains has been achieved with NSC lines because they were selected for their ability to migrate, whereas the engraftment of primary NSCs or those derived from pluripotent stem cells is far less robust. Studies on primary NSC grafts show they tend to spread along white matter tracts with some regional differences, 17,46,112,[115][116][117] as do iPSCderived NSCs, 37 but are much more constrained within brain parenchymal structures. 37,45 However, in LSDs even a small graft secreting normal enzyme into the surrounding parenchyma may mitigate disease pathology in a much larger volume of brain tissue surrounding the engrafted donor cells.…”

Regenerative medicine in Alzheimer's disease

“…With the former, it might be possible to use grafted neural or non-neural stem, and progenitor, cells to deliver protective agents, such as growth factors, or amyloid-degrading molecular therapeutics to reduce burden of extracellular toxic proteins that appear to mediate cognitive functional deficits (e.g. see [23]). However, the prospect of introducing modified or unmodified progenitor cells into relatively healthy patients as a preventative raises the bar for safety to a fairly high standard.…”