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Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system

DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of ins...

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Autores principales: DeRosa, F, Guild, B, Karve, S, Smith, L, Love, K, Dorkin, J R, Kauffman, K J, Zhang, J, Yahalom, B, Anderson, D G, Heartlein, M W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059749/
https://www.ncbi.nlm.nih.gov/pubmed/27356951
http://dx.doi.org/10.1038/gt.2016.46
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author DeRosa, F
Guild, B
Karve, S
Smith, L
Love, K
Dorkin, J R
Kauffman, K J
Zhang, J
Yahalom, B
Anderson, D G
Heartlein, M W
author_facet DeRosa, F
Guild, B
Karve, S
Smith, L
Love, K
Dorkin, J R
Kauffman, K J
Zhang, J
Yahalom, B
Anderson, D G
Heartlein, M W
author_sort DeRosa, F
collection PubMed
description DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice.
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spelling pubmed-50597492016-10-27 Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system DeRosa, F Guild, B Karve, S Smith, L Love, K Dorkin, J R Kauffman, K J Zhang, J Yahalom, B Anderson, D G Heartlein, M W Gene Ther Original Article DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice. Nature Publishing Group 2016-10 2016-06-30 /pmc/articles/PMC5059749/ /pubmed/27356951 http://dx.doi.org/10.1038/gt.2016.46 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
DeRosa, F
Guild, B
Karve, S
Smith, L
Love, K
Dorkin, J R
Kauffman, K J
Zhang, J
Yahalom, B
Anderson, D G
Heartlein, M W
Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title_full Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title_fullStr Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title_full_unstemmed Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title_short Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
title_sort therapeutic efficacy in a hemophilia b model using a biosynthetic mrna liver depot system
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059749/
https://www.ncbi.nlm.nih.gov/pubmed/27356951
http://dx.doi.org/10.1038/gt.2016.46
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