Enabling Widespread, Minimally Invasive Distribution of Multimodal Therapeutic hNSCs throughout the Neuroaxis of ALS Mice
Abstract
The manifestations of most neurological diseases are ultimately the expression of a number of interacting and mutually compounding pathogenic processes; hence, multiple therapeutic targets must be addressed. The neural stem cell (NSC) is well-suited for this challenge. Indeed, the greatest efficacy observed using NSCs in experimental models of neurological disease has come from invoking the multiple therapeutic actions of the stem cell. An exemplar of this was recently evident in our published use of NSCs against a mouse model of amyotrophic lateral sclerosis (ALS), the SOD1G93A mutant mice. The beneficial effects of engrafted NSCs included improved motor performance, respiratory function, histopathology, and symptom-free survival, as well as delayed disease-onset and slowed disease progression. Transplantation of undifferentiated multipotent migratory NSCs into multiple spinal cord sites of early affected adult SOD1G93A mutant mice resulted in extensive integration of donor-derived cells within the ventral horns of many spinal segments. Therapeutic efficacy appeared to be related not only to the number of NSCs engrafted and the expanse of donor NSC distribution but also to the functions subserved by a given engrafted chimeric region (for example, respiration). A meta-analysis indicated that a broader distribution of donor NSCs was associated with greater inhibition of progression of the pathological process, an observation that has given rise to this proposal. What is it that the NSCs did in those segments? Much more impactful than NSC-derived motor neurons (which were actually quite immature) were the NSC-derived non-neuronal cells positioned in close proximity to SOD1G93A motor neurons. NSCs constitutively produced various neurotrophic and neuroprotective molecules (and/or induced their production in the host). These factors, in turn, appeared to promote sparing of host motor neurons and functional neuromuscular units, a reduction in the formation of intraneuronal tangles, a decrease in macrophage/microglial infiltration, a production of supportive wild-type astrocytes, and an alteration in the fate of the progeny generated by mutant host NSCs -- suppression of endogenous toxic mutant astrogliosis with a shift in the host glial population toward protective gray matter oligodendrocytes. What we also learn from this study is that true reconstitution of a central nervous system (CNS) region may fail unless multiple neural cell types are provided, particularly normal non-neurons, which, during development, offer support, guidance, and homeostatic pressure to adjacent neurons. Hence, transplanting NSCs pre-differentiated to solely a neuronal or astroglial lineage may be limiting. Indeed, interventions with a narrow repertoire of action -- whether cells or drugs -- have been minimally successful in ALS, probably because they target only one aspect of a complex pathophysiological cascade. As noted above, the multiple NSC actions described had the greatest impact based on how much of the spinal cord they covered and rendered "chimeric." In this proposal, we will attempt to alter the milieu of the ALS mouse spinal cord as extensively and noninvasively as possible. Indeed, the protection of extant motor neurons and their neuromuscular connections is likely to be more tractable than attempting to repopulate the spinal cord broadly with new yet-to-be integrated motor neurons. Approaches -- whether molecular or cellular -- that have targeted only one pathological mechanism or disease site have repeatedly proven suboptimal. On the other hand, a strategy that impacts a number of pathophysiological processes simultaneously might yield therapeutic synergy. We will test two tricks that we have developed to promote widespread integration of human NSCs (hNSCs) in a non-invasive manner. One is to minimally change the surface of the hNSC by adding a sugar molecule so that it can be administered via the blood stream
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610087
Entities
People
- Evan Snyder
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army