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

Molecular Therapy: Oncolytics

Damian Deavall¹  James B. Rottman²  Joseph C. Glorioso³  Peter Grzesik⁴  Jennifer Lee⁴  Judith Jacques⁴  Christophe Quéva⁴  Daniel Wambua⁴  Lorena Lerner⁴  Jeffrey Bryant⁴  Terry Farkaly⁴  Edward M. Kennedy⁴  Prajna Behara⁴  Caitlin Goshert⁴  Ana De Almeida⁴  Agnieszka Denslow⁴  Mitchell H. Finer⁴  Brian B. Haines⁴  Jacqueline Hewett⁴ 

[1] ApconiX, Alderley Park, Mereside, Macclesfield, UK;Athenaeum Pathology Consulting, LLC, Sudbury, MA, USA;Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA;Oncorus, Inc., Cambridge, MA, USA;

关键词: oncolytic virus;    virotherapy;    HSV-1;    microRNA attenuation;    cancer;    interferon;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown