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Non-viral delivery of chemically modified mRNA to the retina : subretinal versus intravitreal administration

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Abstract
mRNA therapeutics have recently experienced a new wave of interest, mainly due to the discovery that chemical modifications to mRNA's molecular structure could drastically reduce its inherent immunogenicity and perceived instability. On this basis, we aimed to explore the potential of chemically stabilized mRNA for ocular applications. More specifically, we investigated the behavior of mRNA-loaded lipid-based carriers in human retinal cells (in vitro), in bovine retinal explants (ex vivo) and in mouse retinas (in vivo). We demonstrate a clear superiority of mRNA over pDNA to induce protein expression in different retinal cell types, which was further enhanced by chemical modification of the mRNA, providing up to similar to 1800-fold higher reporter gene expression compared to pDNA. Moreover, transgene expression could be detected for at least 20 days after a single administration of chemically modified mRNA in vitro. We furthermore determined the localization and extent of mRNA expression depending on the administration route. After subretinal (SR) administration, mRNA expression was observed in vivo and ex vivo. By contrast, intravitreal (IVT) administration resulted in limited expression in vivo. Using ex vivo bovine explants with an intact vitreoretinal (VR) interface we could attribute this to the inner limiting membrane (ILM), which presents a large barrier for non-viral delivery of mRNA, trapping mRNA complexes at the vitreal side. When the vitreous was removed, which compromises the ILM, mRNA expression was apparent and seemed to colocalize with Muller cells or photoreceptors after respectively IVT or SR administration. Taken together, this study represents a first step towards mRNA-mediated therapy for retinal diseases.
Keywords
Muller cells, Lipoplexes, mRNA, Modified mRNA, pDNA, Ocular, Intravitreal, Subretinal, Drug delivery, Retina, Inner limiting membrane, INTERNAL LIMITING MEMBRANE, TOLL-LIKE RECEPTORS, IN-VITRO, GENE DELIVERY, PROTEIN EXPRESSION, INNATE IMMUNITY, AAV VECTORS, CO-DELIVERY, THERAPY, BARRIER

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MLA
Devoldere, Joke, et al. “Non-Viral Delivery of Chemically Modified MRNA to the Retina : Subretinal versus Intravitreal Administration.” JOURNAL OF CONTROLLED RELEASE, vol. 307, 2019, pp. 315–30, doi:10.1016/j.jconrel.2019.06.042.
APA
Devoldere, J., Peynshaert, K., Dewitte, H., Vanhove, C., De Groef, L., Moons, L., … Remaut, K. (2019). Non-viral delivery of chemically modified mRNA to the retina : subretinal versus intravitreal administration. JOURNAL OF CONTROLLED RELEASE, 307, 315–330. https://doi.org/10.1016/j.jconrel.2019.06.042
Chicago author-date
Devoldere, Joke, Karen Peynshaert, Heleen Dewitte, Christian Vanhove, Lies De Groef, Lieve Moons, Sinem Yilmaz Özcan, Deniz Dalkara, Stefaan De Smedt, and Katrien Remaut. 2019. “Non-Viral Delivery of Chemically Modified MRNA to the Retina : Subretinal versus Intravitreal Administration.” JOURNAL OF CONTROLLED RELEASE 307: 315–30. https://doi.org/10.1016/j.jconrel.2019.06.042.
Chicago author-date (all authors)
Devoldere, Joke, Karen Peynshaert, Heleen Dewitte, Christian Vanhove, Lies De Groef, Lieve Moons, Sinem Yilmaz Özcan, Deniz Dalkara, Stefaan De Smedt, and Katrien Remaut. 2019. “Non-Viral Delivery of Chemically Modified MRNA to the Retina : Subretinal versus Intravitreal Administration.” JOURNAL OF CONTROLLED RELEASE 307: 315–330. doi:10.1016/j.jconrel.2019.06.042.
Vancouver
1.
Devoldere J, Peynshaert K, Dewitte H, Vanhove C, De Groef L, Moons L, et al. Non-viral delivery of chemically modified mRNA to the retina : subretinal versus intravitreal administration. JOURNAL OF CONTROLLED RELEASE. 2019;307:315–30.
IEEE
[1]
J. Devoldere et al., “Non-viral delivery of chemically modified mRNA to the retina : subretinal versus intravitreal administration,” JOURNAL OF CONTROLLED RELEASE, vol. 307, pp. 315–330, 2019.
@article{8622341,
  abstract     = {mRNA therapeutics have recently experienced a new wave of interest, mainly due to the discovery that chemical modifications to mRNA's molecular structure could drastically reduce its inherent immunogenicity and perceived instability. On this basis, we aimed to explore the potential of chemically stabilized mRNA for ocular applications. More specifically, we investigated the behavior of mRNA-loaded lipid-based carriers in human retinal cells (in vitro), in bovine retinal explants (ex vivo) and in mouse retinas (in vivo). We demonstrate a clear superiority of mRNA over pDNA to induce protein expression in different retinal cell types, which was further enhanced by chemical modification of the mRNA, providing up to similar to 1800-fold higher reporter gene expression compared to pDNA. Moreover, transgene expression could be detected for at least 20 days after a single administration of chemically modified mRNA in vitro. We furthermore determined the localization and extent of mRNA expression depending on the administration route. After subretinal (SR) administration, mRNA expression was observed in vivo and ex vivo. By contrast, intravitreal (IVT) administration resulted in limited expression in vivo. Using ex vivo bovine explants with an intact vitreoretinal (VR) interface we could attribute this to the inner limiting membrane (ILM), which presents a large barrier for non-viral delivery of mRNA, trapping mRNA complexes at the vitreal side. When the vitreous was removed, which compromises the ILM, mRNA expression was apparent and seemed to colocalize with Muller cells or photoreceptors after respectively IVT or SR administration. Taken together, this study represents a first step towards mRNA-mediated therapy for retinal diseases.},
  author       = {Devoldere, Joke and Peynshaert, Karen and Dewitte, Heleen and Vanhove, Christian and De Groef, Lies and Moons, Lieve and Özcan, Sinem Yilmaz and Dalkara, Deniz and De Smedt, Stefaan and Remaut, Katrien},
  issn         = {0168-3659},
  journal      = {JOURNAL OF CONTROLLED RELEASE},
  keywords     = {Muller cells,Lipoplexes,mRNA,Modified mRNA,pDNA,Ocular,Intravitreal,Subretinal,Drug delivery,Retina,Inner limiting membrane,INTERNAL LIMITING MEMBRANE,TOLL-LIKE RECEPTORS,IN-VITRO,GENE DELIVERY,PROTEIN EXPRESSION,INNATE IMMUNITY,AAV VECTORS,CO-DELIVERY,THERAPY,BARRIER},
  language     = {eng},
  pages        = {315--330},
  title        = {Non-viral delivery of chemically modified mRNA to the retina : subretinal versus intravitreal administration},
  url          = {http://dx.doi.org/10.1016/j.jconrel.2019.06.042},
  volume       = {307},
  year         = {2019},
}

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