SBIR-STTR Award

Modulation of the inflammatory cascade by several diverse strategies including A immunization, non-steroidal anti-inflammatory drug (NSAID) administration, and manipulation of microglial activation states have all been shown to reduce Alzheimer disease (AD)-like pathology, and cognitive deficits in AD transgenic mouse models. Our recent study demonstrated amelioration of AD-like pathology in PSAPP (APPswe, PSEN1dE9) mice when multiply injected with low dose of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name "U-CORD-CELLTM"), a well known immunomodulator. This was observed through marked reduction of A?/?-amyloid plaques and associated astrocytosis. In concert with this down-regulation of pro-inflammatory signaling, cultured microglia isolated from HUCBC-infused PSAPP mice demonstrated increased A? phagocytic activity, thus clearly demonstrating HUCBC's potential immunomodulatory property. Although a typical reduction in cerebral A? plaque burden has been associated with an improvement in cognition, regarded as the true sign of improvement in AD, our study did not address either the behavioral or the cognitive changes associated with HUCBC injections. Thus, in this proposal we would like to test if HUCBC infusion can promote a rescue of behavioral and cognitive deficits and correlate these changes with their pathological improvements in PSAPP mice. Furthermore, we also plan to infuse these mice with human adult mononuclear fractions to demonstrate specific need for HUCBC rather than the adult mononuclear cells in order to observe these immunomodulatory and therapeutic effects. Based on these combined lines of evidence and our recent study, we hypothesize that multiple low dose injections of U-CORD-CELL" into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD.Project Narrative - Relevance to public health. In summary, we hypothesize that multiple low dose injections of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name U-CORD-CELL") into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD

In the past years, we have shown that human umbilical cord blood cells (HUCBC, U-CORD- CELL") provide cognitive recovery in animal models of neurodegenerative disease. Infusion of HUCBC resulted in reduced infarct volume as well as in rescue of behavioral benefits in an animal model of stroke. We further showed that HUCBC infusion proved to be beneficial in animal models of Parkinson's disease, and amyotropic lateral sclerosis. Our latest study showed that multiple low dose injections of HUCBC in Alzheimer's disease (AD) mouse models caused a reduction in cerebral Ab levels/b-amyloid deposits which further resulted in increased serum levels of Ab1-40, 42, thus suggesting efflux from the CNS. Furthermore, there was a reduction of Ab-specific neurototoxic T lymphocyte responses which corresponded with elevated CNS/serum levels of anti-inflammatory (IL- 10 and TGF-b1), and decreased pro-inflammatory cytokines (IL-1b and TNF-a). Both in vitro and in vivo studies demonstrated that CD40-CD40L signaling modulation by HUCBC was critical to this therapeutic outcome. Indeed we observed a decreased soluble CD40L serum level and decreased microglial CD40 expression. In the past we have fully characterized CD40 involvement in AD mice. As expected, complete blockade or genetic ablation results in reductions in brain amyloid. However, this complete blockade could also result in various immunodeficiencies. Thus specific CD40 immunomodulation by HUCBC, rather than complete systemic blockade, would be highly desired. This is because HUCBC specifically modulate host responses by not only dampening CD40 interactions but by also inducing endogenous mechanisms that reverse polarized Th1 cytokine responses and up-regulate microglial Ab phagocytic activity. It is currently believed that upregulated CD40 and CD40L expression in collaboration with cerebral Ab deposits promote cerebral amyloid angiopathy (CAA). Our study found a marked reduction of CAA and microhemorrhage. The latter is most likely supported by the fact of increased pool of both naove and regulatory T cells following the HUCBC injection. This increased pool raises the tolerance and further promotes immune inactivation. Lastly, our pilot study analyzed cognitive changes associated with HUCBC infusion and revealed a partial improvement in cognitive deficits, specifically resulting in improved working memory. Additional studies showed that HUCBC induce production of host neurotrophins including NGF, BDNF, GDNF, and NT2/3. HUCBC transplantation is practical and already being used clinically against various lymphomas and systemic lupus. Numerous studies have demonstrated HUCBC are very weakly immunogenic due to their immature or complete lack of, hematopoietic and endothelial markers such as CD14, CD34, CD45 and CD31. They also are devoid of MHC II, major co-stimulatory molecules (CD80, CD86, CD40, CD40L), and have a significant counts of both naove and regulatory T cells;all of which will push the endogenous system towards tolerance and negating the possibility of any type of rejection, GVHD, or need for pretreatment immunosuppression. Further, HUCBC are relatively inexpensive, readily accessible, do not require full HLA matching, and do not pose the ethical concerns associated with cells of embryonic origin. Here we plan to fully characterize the optimal dosing time points and duration which provide maximal anti-AD like effects behaviorally and histologically. We will administer multiple low dose injections of U-CORD-CELL"" to AD transgenic PSAPP mice at different disease stages and subject the animals to our established behavioral and histological analyses. Further the safety of these cells as a potential therapeutic approach will be examined in two species. Because it is our long-term goal to move U-CORD-CELL"" into human trials for patients with mild to moderate AD, the proposal culminates in a completed investigational new drug (IND) application for submission to the FDA. , ,

Public Health Relevance:
Human umbilical cord blood cells (HUCBC, U-CORD-CELL"") have emerged as very effective and relatively safe immune system modulator and neuroprotector. Their benefits have already been well demonstrated in animal models of neurodegenerative disease including: Alzheimer's disease (AD), Parkinson's disease, age-related macular degeneration, amyotropic lateral sclerosis (ALS), and stroke. Although we previously showed their safety and efficacy in an animal model of Alzheimer's disease, we did not look at the long term effects on safety nor the potential of starting this treatment regiment at different disease stages. Hence here, we would like to test full efficacy of this therapeutic approach during different disease stages in Alzheimer mice and pay close attention at the safety following both short and long term treatments. We feel confident, based on our previous findings that this therapeutic approach will prove both efficacious and relatively safe and thus allow us to move it one step closer to clinical trials.

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