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Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections

There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) ta...

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Autores principales: Iversen, Patrick L., Warren, Travis K., Wells, Jay B., Garza, Nicole L., Mourich, Dan V., Welch, Lisa S., Panchal, Rekha G., Bavari, Sina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509674/
https://www.ncbi.nlm.nih.gov/pubmed/23202506
http://dx.doi.org/10.3390/v4112806
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author Iversen, Patrick L.
Warren, Travis K.
Wells, Jay B.
Garza, Nicole L.
Mourich, Dan V.
Welch, Lisa S.
Panchal, Rekha G.
Bavari, Sina
author_facet Iversen, Patrick L.
Warren, Travis K.
Wells, Jay B.
Garza, Nicole L.
Mourich, Dan V.
Welch, Lisa S.
Panchal, Rekha G.
Bavari, Sina
author_sort Iversen, Patrick L.
collection PubMed
description There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates.
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spelling pubmed-35096742012-12-10 Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections Iversen, Patrick L. Warren, Travis K. Wells, Jay B. Garza, Nicole L. Mourich, Dan V. Welch, Lisa S. Panchal, Rekha G. Bavari, Sina Viruses Article There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates. MDPI 2012-11-06 /pmc/articles/PMC3509674/ /pubmed/23202506 http://dx.doi.org/10.3390/v4112806 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Iversen, Patrick L.
Warren, Travis K.
Wells, Jay B.
Garza, Nicole L.
Mourich, Dan V.
Welch, Lisa S.
Panchal, Rekha G.
Bavari, Sina
Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title_full Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title_fullStr Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title_full_unstemmed Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title_short Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
title_sort discovery and early development of avi-7537 and avi-7288 for the treatment of ebola virus and marburg virus infections
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509674/
https://www.ncbi.nlm.nih.gov/pubmed/23202506
http://dx.doi.org/10.3390/v4112806
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