Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage

Anne Zebitz Eriksen, Rasmus Eliasen, Julia Oswald, Paul J. Kempen, Fredrik Melander, Thomas Lars Andresen, Michael Young, Petr Baranov, Andrew J. Urquhart*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

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    Abstract

    A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including: i) activating/inhibiting cell pathways synergistically; ii) avoiding tumorigenesis and iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic and lipopeptide phosphatase tension homolog inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-D-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs lead to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.
    Original languageEnglish
    JournalA C S Nano
    Volume12
    Issue number8
    Pages (from-to)7497-7508
    Number of pages12
    ISSN1936-0851
    DOIs
    Publication statusPublished - 2018

    Bibliographical note

    This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

    Keywords

    • Retina
    • Liposomes
    • Neuropathy
    • Neuroprotection
    • Ganglion
    • Transplant

    Cite this

    @article{a0147284c7b84d29a73dabdbd7b2f3e6,
    title = "Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage",
    abstract = "A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including: i) activating/inhibiting cell pathways synergistically; ii) avoiding tumorigenesis and iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic and lipopeptide phosphatase tension homolog inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-D-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs lead to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.",
    keywords = "Retina, Liposomes, Neuropathy, Neuroprotection, Ganglion, Transplant",
    author = "Eriksen, {Anne Zebitz} and Rasmus Eliasen and Julia Oswald and Kempen, {Paul J.} and Fredrik Melander and Andresen, {Thomas Lars} and Michael Young and Petr Baranov and Urquhart, {Andrew J.}",
    note = "This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.",
    year = "2018",
    doi = "10.1021/acsnano.8b00596",
    language = "English",
    volume = "12",
    pages = "7497--7508",
    journal = "A C S Nano",
    issn = "1936-0851",
    publisher = "American Chemical Society",
    number = "8",

    }

    Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage. / Eriksen, Anne Zebitz; Eliasen, Rasmus; Oswald, Julia; Kempen, Paul J.; Melander, Fredrik; Andresen, Thomas Lars; Young, Michael; Baranov, Petr; Urquhart, Andrew J.

    In: A C S Nano, Vol. 12, No. 8, 2018, p. 7497-7508.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage

    AU - Eriksen, Anne Zebitz

    AU - Eliasen, Rasmus

    AU - Oswald, Julia

    AU - Kempen, Paul J.

    AU - Melander, Fredrik

    AU - Andresen, Thomas Lars

    AU - Young, Michael

    AU - Baranov, Petr

    AU - Urquhart, Andrew J.

    N1 - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

    PY - 2018

    Y1 - 2018

    N2 - A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including: i) activating/inhibiting cell pathways synergistically; ii) avoiding tumorigenesis and iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic and lipopeptide phosphatase tension homolog inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-D-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs lead to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.

    AB - A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including: i) activating/inhibiting cell pathways synergistically; ii) avoiding tumorigenesis and iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic and lipopeptide phosphatase tension homolog inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-D-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs lead to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.

    KW - Retina

    KW - Liposomes

    KW - Neuropathy

    KW - Neuroprotection

    KW - Ganglion

    KW - Transplant

    U2 - 10.1021/acsnano.8b00596

    DO - 10.1021/acsnano.8b00596

    M3 - Journal article

    VL - 12

    SP - 7497

    EP - 7508

    JO - A C S Nano

    JF - A C S Nano

    SN - 1936-0851

    IS - 8

    ER -