Neural Stem Cell Transplantation: A Novel Cellular Therapy for Alzheimer's Disease

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Program Summary/Abstract This U01 proposal is designed to provide the preclinical framework required to advance a novel stem cell therapy to human clinical trials as an effective treatment for Alzheimer's disease (AD). AD is the most prevalent age-related neurodegenerative disorder and leading cause of dementia, affecting an estimated 5.3 million people in the U.S. There is no cure and no means of prevention. To date, a handful of traditional, single-target pharmacological approaches have produced only marginal clinical improvements - there is a critical need for more effective therapies. Therefore, the long-term goal of our research is to develop a disease-modifying cellular therapy for AD that will have a meaningful impact on patients' lives. Cellular therapies target multiple disease mechanisms and provide a multifaceted approach to treat the complex pathologies associated with AD. In collaboration with Neuralstem, Inc., we have developed a unique line of human cortex-derived neural stem cells (NSCs) that produce several neuroprotective growth factors. Our findings to date, as well as proof- of- concept studies by others, show the benefit of cell therapies in AD models and indicate that efficacy is enhanced when coupled with delivery of trophic factors. In our proposed approach, NSC transplantation will combine the multifactorial therapeutic potential of a cellular therapy with sustained and directed delivery of neurotrophic factors, providing increased benefit compared to traditional approaches and improving outcomes in AD. Our preliminary data in a mouse model demonstrate that NSC transplantation is safe and effective, significantly impacting cognition and reducing Aβ plaque burden. In this proposal, we will determine the maximum tolerated dose and assess NSC bio-distribution and tissue tropism in two well-established and highly relevant mouse models: 5XFAD and rTg4510. We will then perform large-scale efficacy testing of NSCs in these mouse models and complete a dose-response feasibility study in non-human primates, which are anatomically and cognitively more relevant to human clinical testing. Overall, our proposal will have a significant impact on AD by providing proof-of-concept efficacy data for a well-characterized cellular therapy in two relevant mouse models and safety data in a large animal with a brain structure that is more analogous to humans. Completion of our proposed IND-enabling studies, as well as our laboratory's unique track record of translating proof-of-principle animal studies to human trials, will enable this stem cell therapy to progress into an attainable disease-modifying intervention for AD patients.