More than 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed to two major factors: 1) most therapeutics focus on a single secondary injury mechanism, and 2) testing in rodent models alone may not be adequate for predicting which treatment is going to be successful. We will combine two unique enabling technologies to address these caveats by using a neural stem cell (NSC) derived biologic product, called NPEX? to address multiple secondary injury mechanisms and long-term regenerative affects in an established pig model of ischemic stroke. By expanding on positive data obtained in the mouse model of embolic stroke, we will address both the STAIR and STEPS committee?s guidance that a positive outcome should be replicated in a second species and another stroke model. Work from our group and others support that NSC transplants provide benefit when transplanted into rodent or pig brains following stroke. However, transplanted cells are not integrating into host tissue, but providing an immediate paracrine benefit. It is reasonable that these improvements are stimulated by factors provided by the NSC, like small signaling vesicles produced by the cells and released into the local milieu, in the case of ArunA?s proprietary NSC?s they are called NPEX?. The goal of the proposed research is to determine if NPEX? provide neuroprotective and/or regenerative benefits after stroke, in an established pig model of stroke that shares many important physiological characteristics with humans. These include having a more evolutionarily complex, larger gyrencephalic brain, and similar gray and white matter composition to the human brain. These similarities make the porcine model an excellent secondary stroke model, allowing ArunA to expedite the proof of concept studies required to assess the therapeutic potential of NPEX? following human stroke. The nanometer scale size of NPEX? is a huge advantage over traditional cell therapies because they can be continuously produced in large quantities, from cells manufactured in a relatively small footprint, using a streamlined process that has already supported 12 years of commercial cell manufacturing. NPEX can be produced as an off the shelf product that can be thawed and injected intravenously or into cerebral spinal fluid directly, and can be administered in multiple doses, as opposed to NSC therapy, thus supporting the recovery of the injured brain over time as opposed to a bolus following cell injection. ArunA?s ability to pursue phase II funding and commercial investment is more attainable by addressing proof of concept studies that tackle known impediments in the early stages of product development. Toward this goal, ArunA has engaged Biologics Inc. (see letter) to develop a gap analysis and roadmap to IND filing as well as clinical trials. Success in the pig stroke model positions ArunA as the only entity able to produce NPEX? at a scale facilitating large animal studies, and provides crucial information needed to proceed to the next IND-enabling studies.

Public Health Relevance

The goal of the proposed research is to determine if neural stem cell derived signaling vesicles, called NPEX?, provide neuroprotective and/or regenerative benefits following stroke. These characteristics will be evaluated in an established pig model of stroke that shares many important neurophysiological similarities with humans, providing a clear assessment of therapeutic potential for human stroke. These proof of concept studies will help ArunA Biomedical establish a path for regulatory discussions with the FDA and secure commercial investment for production of exosome therapeutics on a commercial scale.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Fertig, Stephanie
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Aruna Biomedical, Inc.
United States
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Webb, Robin L; Kaiser, Erin E; Jurgielewicz, Brian J et al. (2018) Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke. Stroke 49:1248-1256