Novel Highly Regenerative and Scalable Progenitor Cell Exosomes for Treating Stroke

ABSTRACT
Stroke is a leading cause of disability worldwideGloballythere aremillion stroke survivors each year who
have significant neurological deficits including sensory and motor disabilityleading to excessive socioeconomic
burdenCell therapy using primary MSCs has been actively explored by us and others as a therapeutic solution
to this unmet medical needHoweversince the therapeutic efficacy of MSCs has been shown to be dependent
on intercellular communication between administered cells and brain parenchymawe reasoned that the
exosomesnanoscale extracellular vesiclesthat cells secrete to transmit this information could be used instead
of and perhaps more efficiently than the cells themselvesIndeedwe were the first to report that systemic
delivery of exosomes released by mesenchymal stromal cellsMSCsto rats subjected to stroke or traumatic
brain injuryTBIsubstantially improves recovery of neurological functionA key rationale for using exosomes is
that they obviate many of the risks associated with cell therapy because their use concentrates the active
component of stem cells in a simpler compact non replicative formImportantlythey can cross the BBB allowing
systemic delivery for treating the injured brainMoreoverexosomes have low risk of immune rejection and are
likely to be more cost effective to produce and convenient to use and store and thus have potential for anoffthe shelftreatmentHoweverthere are significant roadblocks to translation of our preclinical results using MSC
exosomes because of inherent limitations of MSCs for industrial scale productionMSCs are a poorly defined
heterogeneous cell population with low proliferative capacity which can hinder batch consistency and limit scaleup for exosome productionThus to overcome these roadblockswe propose here to use exosomes derived
from BioTime s clonally pure PureStemprogenitor cell lineswhich have a high degree of homogeneity and are
highly proliferative and regenerative because of their early embryonic originThe goal of this phase I proposal is
to conduct a feasibility study that would demonstrate neurological recovery in our rat stroke model using
PureStem exosomesWe propose to identifyPureStem derived candidate exosomes based on angiogenic
activity and micro RNA and protein content because increasing angiogenesis in the ischemic brain facilitates
improvement of neurological function after strokeThelead candidates will be tested for efficacy measured by
neurological function in our rat middle cerebral artery occlusionMCAOmodelEvidence of feasibility using our
well established model to mimic human stroke and using exosomes from a scalable PureStem cell line will pave
the way for further preclinical development and IND enabling studies in phase II NARRATIVE
Stroke is a leading cause of disability worldwidestroke induced angiogenesis and associated neurogenesis are
limitedthus limiting the functional recoveryExosomes cross the blood brain barrierBBBand enhance
angiogenesis by delivering functional cargo to trigger gene expression in specific recipient cell types in the brainThus we propose to employ exosomes to improve neurological function after strokeWe are developing
exosomes derived from BioTime s clonally pure Purestemprogenitor stem cell lineswhich have a high degree
of homogeneity and are highly proliferative and regenerativeThe goal of this phase I proposal is to demonstrate
feasibility by selecting candidate exosome production cell lines from our library and demonstrating efficacy of
candidate exosomes on improvement of neurological outcomes in a clinically relevant animal model of embolic
strokemiddle cerebral artery occlusionMACO