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    Advancing Extracellular Vesicle Therapeutics Into Clinical Trials For Central Nervous System Disorders

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    Athenaeum Scientific Publishers
    In December 2023, the US Food and Drug Administration released a draft guidance document titled “Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for Industry” for public comment [1]. Potency assays are arguably the most problematic analytic release assay to develop for cell and cell derivate products, including Extracellular Vesicles (EV). EVs are produced by many cell types and harbor parent cell-specific bioactive cargoes including proteins and nucleic acids. They are u

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    Advancing Extracellular Vesicle Therapeutics Into Clinical Trials For Central Nervous System Disorders

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    Athenaeum Scientific Publishers
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    In December 2023, the US Food and Drug Administration released a draft guidance document titled “Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for Industry” for public comment [1]. Potency assays are arguably the most problematic analytic release assay to develop for cell and cell derivate products, including Extracellular Vesicles (EV). EVs are produced by many cell types and harbor parent cell-specific bioactive cargoes including proteins and nucleic acids. They are u

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    Advancing Extracellular Vesicle Therapeutics Into Clinical Trials for Central Nervous System Disorders

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    In December 2023, the US Food and Drug Administration released a draft guidance document titled “Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for Industry” for public comment [1]. Potency assays are arguably the most problematic analytic release assay to develop for cell and cell derivate products, including Extracellular Vesicles (EV). EVs are produced by many cell types and harbor parent cell-specific bioactive cargoes including proteins and nucleic acids. They are u

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    42 views2 pages

    Advancing Extracellular Vesicle Therapeutics Into Clinical Trials For Central Nervous System Disorders

    Uploaded by

    Athenaeum Scientific Publishers
    In December 2023, the US Food and Drug Administration released a draft guidance document titled “Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for Industry” for public comment [1]. Potency assays are arguably the most problematic analytic release assay to develop for cell and cell derivate products, including Extracellular Vesicles (EV). EVs are produced by many cell types and harbor parent cell-specific bioactive cargoes including proteins and nucleic acids. They are u

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 2

    Short Commentary

    Advancing Extracellular Vesicle Therapeutics into Clinical Trials for


    Central Nervous System Disorders
    Steven L Stice1,2*, Emily W Baker2, Viviana Martinez Hamilton2, Raymond L Swetenburg2
    1Regenerative
    Bioscience Center, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA USA
    2Aruna Bio Inc, Athens, GA USA

    *Correspondence author: Steven L Stice, Regenerative Bioscience Center, College of Agricultural and Environmental Sciences, University of Georgia, Athens,
    GA USA and Aruna Bio Inc, Athens, GA USA; Email: [email protected]

    Commentary
    Citation: Stice SL, et al. Advancing In December 2023, the US Food and Drug Administration released a draft guidance document
    Extracellular Vesicle Therapeutics
    titled “Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for
    into Clinical Trials for Central
    Industry” for public comment [1]. Potency assays are arguably the most problematic analytic
    Nervous System Disorders. J Reg
    Med Biol Res. 2024;5(1):1-2. release assay to develop for cell and cell derivate products, including Extracellular Vesicles
    https://doi.org/10.46889/JRMBR.2024.
    (EV). EVs are produced by many cell types and harbor parent cell-specific bioactive cargoes
    5101 including proteins and nucleic acids. They are unique intercellular signaling particles that can
    act as both the messenger and/or effector in recipient cells. We and others have shown that
    Received Date: 06-01-2024
    Neural Stem Cell EVs (NSC EVs) derived in bioreactors have therapeutic potential for treating
    neurological disease and Acute Ischemic Stroke (AIS). New FDA Investigational New Drug
    Accepted Date: 22-01-2024
    (IND) applications are being filed and specifically, we have an IND application for AIS. As the
    Published Date: 30-01-2024
    field grows, new INDs will be filed for various other therapeutic indications. In order for EV
    therapeutics to move efficiently through the regulatory process to approval, there is a need for
    more emphasis on and development of analytical assays directly related to complex and likely
    multimodal, mechanisms of action. Research focused on this area will lead to new disease-
    Copyright: © 2024 by the authors.
    Submitted for possible open access specific potency assays and identification of critical quality attributes.
    publication under the terms and
    conditions of the Creative CommonsPotency assays for EVs are essential for defining the bioactivity, quality, batch-to-batch
    Attribution (CCBY) license
    reproducibility and stability of EV preparations and to facilitate subsequent EV use as
    (https://creativecommons.org/li therapeutics or carriers for cell-free therapies. Potency assays are performed as part of product
    censes/by/4.0/).
    release, comparability studies and stability testing. Although potency assays are just one of
    many important analytic assays needed to ensure progress through clinical trials, these are
    often the most difficult to implement. A relevant set of potency assays needs to be linked to the
    mechanism of action for a therapeutic. A recent study published as a preprint describes the
    development of a ubiquitous enzymatic-based assay for EVs, a single-step functional analysis to predict potency and to
    quantitatively measure EV-bioactivity and vesicle integrity, using small-size EV samples [2]. It is highly likely that potency assays
    will need to be built around the mechanism of action for specific therapeutic applications and we look forward to more
    publications on potential potency assays in this manner.

    Early-stage potency bioassays are typically based on pathophysiological mechanisms and implicated pathways in early
    preclinical studies to identify potential EV mechanism(s) of action. Thus, ideally there is an initiating factor(s) that creates the
    signal that indicates biological activity, the dose response, as well as the duration of the response, all of which must be measurable
    in the bioassay. In the case of a bioassay, the process requires choosing a cell line and type that is relevant to the EVs mechanism
    of action. If there are multiple mechanisms of action, this may require use of additional cell lines. Qualifying the operating
    conditions is necessary for any assay, including but not limited to cell density, incubation time and temperature. This will ensure
    a rigorous, robust and reproducible assay, as the potency assay(s) will need to be further validated for specificity, accuracy,
    precision and linearity throughout therapeutic development.
    https://doi.org/10.46889/JRMBR.2024.5101 https://athenaeumpub.com/journal-of-regenerative-medicine-biology-research/
    2

    As AIS therapy using NSC EVs moves forward, potency assays built around the mechanisms of action will play an important
    role in the regulatory approval process. A good potency assay starts with an understanding of the therapeutic activity of EVs [3-
    5]. For example, a mechanism of action of NSC EVs for AIS and potentially any disease propagated by cell damage, is to convert
    damaging extracellular ATP to anti-inflammatory adenosine. Also, NSC EVs reduce pro- inflammatory C-C Motif Chemokine
    Ligand 2 (CCL2) levels and promote an anti-inflammatory phenotype in circulating immune cells leading to reduced stroke
    lesion size and improved functional recovery. NSC EVs suppress multiple cell death signaling cascades in the central nervous
    system microenvironment. Cellular and/or acellular assays will translate these in vivo mechanisms of action to a quantifiable
    and reproducible output to ensure potency of each NSC EV lot.

    Beyond AIS, one of the most promising applications of NSC EVs is in the treatment of Amyotrophic Lateral Sclerosis (ALS). ALS
    is a neurodegenerative disease that affects the motor neurons in the brain and spinal cord. In a preliminary study, we have shown
    that NSC EVs significantly preserved motor function, decreased serum neurofilament light chain and prolonged survival in ALS
    mice. NSC EVs also reduced inflammatory mediators TNFα, IL-1β, IL-6, RIPK1 and NLRP3 in the lumbar spinal. These results
    suggest that NSC EVs have the potential to be developed as a therapeutic for ALS. The complex pathogenesis in the central
    nervous system during ALS suggests the need to develop drugs with multimodal therapeutic action and will likely require the
    development of multiple potency assays relevant to the active agents in and on the surface of the NSC EVs.

    NSC EVs are under development as a therapeutic for neurodegenerative diseases and AIS. The therapeutic activity of NSC EVs
    has been demonstrated in vitro as well as in multiple AIS models. We are building on these findings to develop robust potency
    assays in an effort to avoid the translational pitfalls many cell therapies have encountered in clinical trials. Further studies are
    needed to determine the safety and efficacy of NSC EVs in humans and will be guided by advances in understanding how the
    therapeutic EVs act in these specific diseases. Relevant potency assays based on mechanism of action will be essential for the
    progression of NSC EV therapies through the clinic to the patients that need them.

    Keywords: Acute Ischemic Stroke; Extracellular Vesicles; Gene Therapy; Neural Stem Cell

    Conflict of Interest
    The authors have no conflict of interest to declare.

    References
    1. United States Food and Drug Administration Center for Biologics Evaluation and Research. 2019.
    2. Potency assurance for cellular and gene therapy products. Draft Guidance for Industry. 2023.
    3. Adamo G, Picciotto S, Gargano P, Paterna A, Rao E, Raccosta S, et al. Functional enzymatic assays to predict the potency of extracellular
    vesicles. bioRxiv. 2023;2023-10.
    4. Webb RL, Kaiser EE, Scoville SL, Thompson TA, Fatima S, Pandya C, et al. Human neural stem cell extracellular vesicles improve tissue
    and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res. 2018;9:530-9.
    5. Webb RL, Kaiser EE, Jurgielewicz BJ, Spellicy S, Scoville SL, Thompson TA, et al. Human neural stem cell extracellular vesicles improve
    recovery in a porcine model of ischemic stroke. Stroke. 2018;49(5):1248-56.
    6. Spellicy SE, Kaiser EE, Bowler MM, Jurgielewicz BJ, Webb RL, West FD, et al. Neural stem cell extracellular vesicles disrupt midline shift
    predictive outcomes in porcine ischemic stroke model. Transl Stroke Res. 2020;11:776-88.

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    https://doi.org/10.46889/JRMBR.2024.5101 https://athenaeumpub.com/journal-of-regenerative-medicine-biology-research/

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