Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability

Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single cop...

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Main Authors:	Edward M. Kennedy, Terry Farkaly, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Hewett, Jeffrey Bryant, Prajna Behara, Caitlin Goshert, Daniel Wambua, Ana De Almeida, Judith Jacques, Damian Deavall, James B. Rottman, Joseph C. Glorioso, Mitchell H. Finer, Brian B. Haines, Christophe Quéva, Lorena Lerner
Format:	Article
Language:	English
Published:	Elsevier 2020-09-01
Series:	Molecular Therapy: Oncolytics
Subjects:	oncolytic virus virotherapy HSV-1 microRNA attenuation cancer interferon
Online Access:	http://www.sciencedirect.com/science/article/pii/S2372770520301212

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spelling	doaj-b74418f2850d47de82488eefe949e0242020-11-25T03:32:02ZengElsevierMolecular Therapy: Oncolytics2372-77052020-09-0118476490Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved TolerabilityEdward M. Kennedy0Terry Farkaly1Peter Grzesik2Jennifer Lee3Agnieszka Denslow4Jacqueline Hewett5Jeffrey Bryant6Prajna Behara7Caitlin Goshert8Daniel Wambua9Ana De Almeida10Judith Jacques11Damian Deavall12James B. Rottman13Joseph C. Glorioso14Mitchell H. Finer15Brian B. Haines16Christophe Quéva17Lorena Lerner18Oncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAApconiX, Alderley Park, Mereside, Macclesfield, UKAthenaeum Pathology Consulting, LLC, Sudbury, MA, USADepartment of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USAOncorus, Inc., Cambridge, MA, USA; Corresponding author: Lorena Lerner, PhD, Oncorus, Inc., 50 Hampshire Street, Suite 401, Cambridge, MA 02139, USA.Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo, this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1.http://www.sciencedirect.com/science/article/pii/S2372770520301212oncolytic virusvirotherapyHSV-1microRNA attenuationcancerinterferon
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Edward M. Kennedy Terry Farkaly Peter Grzesik Jennifer Lee Agnieszka Denslow Jacqueline Hewett Jeffrey Bryant Prajna Behara Caitlin Goshert Daniel Wambua Ana De Almeida Judith Jacques Damian Deavall James B. Rottman Joseph C. Glorioso Mitchell H. Finer Brian B. Haines Christophe Quéva Lorena Lerner
spellingShingle	Edward M. Kennedy Terry Farkaly Peter Grzesik Jennifer Lee Agnieszka Denslow Jacqueline Hewett Jeffrey Bryant Prajna Behara Caitlin Goshert Daniel Wambua Ana De Almeida Judith Jacques Damian Deavall James B. Rottman Joseph C. Glorioso Mitchell H. Finer Brian B. Haines Christophe Quéva Lorena Lerner Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability Molecular Therapy: Oncolytics oncolytic virus virotherapy HSV-1 microRNA attenuation cancer interferon
author_facet	Edward M. Kennedy Terry Farkaly Peter Grzesik Jennifer Lee Agnieszka Denslow Jacqueline Hewett Jeffrey Bryant Prajna Behara Caitlin Goshert Daniel Wambua Ana De Almeida Judith Jacques Damian Deavall James B. Rottman Joseph C. Glorioso Mitchell H. Finer Brian B. Haines Christophe Quéva Lorena Lerner
author_sort	Edward M. Kennedy
title	Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
title_short	Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
title_full	Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
title_fullStr	Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
title_full_unstemmed	Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability
title_sort	design of an interferon-resistant oncolytic hsv-1 incorporating redundant safety modalities for improved tolerability
publisher	Elsevier
series	Molecular Therapy: Oncolytics
issn	2372-7705
publishDate	2020-09-01
description	Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo, this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1.
topic	oncolytic virus virotherapy HSV-1 microRNA attenuation cancer interferon
url	http://www.sciencedirect.com/science/article/pii/S2372770520301212
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Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability

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