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Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles

Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable s...

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Autores principales: Chen, Chun-Yu, Tran, Dominic M., Cavedon, Alex, Cai, Xiaohe, Rajendran, Raj, Lyle, Meghan J., Martini, Paolo G.V., Miao, Carol H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178004/
https://www.ncbi.nlm.nih.gov/pubmed/32330871
http://dx.doi.org/10.1016/j.omtn.2020.03.015
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author Chen, Chun-Yu
Tran, Dominic M.
Cavedon, Alex
Cai, Xiaohe
Rajendran, Raj
Lyle, Meghan J.
Martini, Paolo G.V.
Miao, Carol H.
author_facet Chen, Chun-Yu
Tran, Dominic M.
Cavedon, Alex
Cai, Xiaohe
Rajendran, Raj
Lyle, Meghan J.
Martini, Paolo G.V.
Miao, Carol H.
author_sort Chen, Chun-Yu
collection PubMed
description Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable system to efficiently package and deliver mRNA to the target site. Mice intravenously infused with the luciferase mRNA LNPs showed luminescence signals predominantly in the liver 4 h after injection. Repeated injections of LNPs did not induce elevation of liver transaminases. We next injected LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) into HemA mice. A single injection of B domain-deleted F8 LNPs using different dosing regimens achieved a wide range of therapeutic activities rapidly, which can be beneficial for various usages in hemophilia treatment. The expression slowly declined yet remained above therapeutic levels up to 5–7 days post-injection. Furthermore, routine repeated injections of F8 LNPs in immunodeficient mice produced consistent expression of FVIII over time. In conclusion, F8 LNP treatment produced rapid and prolonged duration of FVIII expression that could be applied to prophylactic treatment and potentially various other treatment options. Our study showed potential for a safe and effective platform of new mRNA therapies for HemA.
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spelling pubmed-71780042020-06-23 Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles Chen, Chun-Yu Tran, Dominic M. Cavedon, Alex Cai, Xiaohe Rajendran, Raj Lyle, Meghan J. Martini, Paolo G.V. Miao, Carol H. Mol Ther Nucleic Acids Article Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable system to efficiently package and deliver mRNA to the target site. Mice intravenously infused with the luciferase mRNA LNPs showed luminescence signals predominantly in the liver 4 h after injection. Repeated injections of LNPs did not induce elevation of liver transaminases. We next injected LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) into HemA mice. A single injection of B domain-deleted F8 LNPs using different dosing regimens achieved a wide range of therapeutic activities rapidly, which can be beneficial for various usages in hemophilia treatment. The expression slowly declined yet remained above therapeutic levels up to 5–7 days post-injection. Furthermore, routine repeated injections of F8 LNPs in immunodeficient mice produced consistent expression of FVIII over time. In conclusion, F8 LNP treatment produced rapid and prolonged duration of FVIII expression that could be applied to prophylactic treatment and potentially various other treatment options. Our study showed potential for a safe and effective platform of new mRNA therapies for HemA. American Society of Gene & Cell Therapy 2020-04-07 /pmc/articles/PMC7178004/ /pubmed/32330871 http://dx.doi.org/10.1016/j.omtn.2020.03.015 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Chen, Chun-Yu
Tran, Dominic M.
Cavedon, Alex
Cai, Xiaohe
Rajendran, Raj
Lyle, Meghan J.
Martini, Paolo G.V.
Miao, Carol H.
Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title_full Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title_fullStr Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title_full_unstemmed Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title_short Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
title_sort treatment of hemophilia a using factor viii messenger rna lipid nanoparticles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178004/
https://www.ncbi.nlm.nih.gov/pubmed/32330871
http://dx.doi.org/10.1016/j.omtn.2020.03.015
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