Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates
| Autor: | Justin C. Roth, G. Yancey Gillespie, Jackie N. Parker, James O. Peggins, Kathleen H. Price, Nicholas W. Powers, Jennifer M. Coleman, Steven L. Carroll, Richard J. Whitley, Sheila D. Grimes, James M. Markert, Kevin A. Cassady, Patricia E. Noker, James J. Cody |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Biodistribution viruses Herpesvirus 1 Human Biology Virus Replication medicine.disease_cause Virus Glioma medicine Animals Pre-Clinical Safety Studies Genetics (clinical) Oncolytic Virotherapy Brain Neoplasms Extramural Drug Administration Routes medicine.disease Interleukin-12 Virology Oncolytic virus Infusions Intraventricular Herpes simplex virus Viral replication Interleukin 12 Aotidae Female |
| Zdroj: | Human Gene Therapy Clinical Development. 25:16-27 |
| ISSN: | 2324-8645 2324-8637 |
| Popis: | Herpes simplex virus type 1 (HSV-1) mutants lacking the γ(1)34.5 neurovirulence loci are promising agents for treating malignant glioma. Arming oncolytic HSV-1 to express immunostimulatory genes may potentiate therapeutic efficacy. We have previously demonstrated improved preclinical efficacy, biodistribution, and safety of M002, a γ(1)34.5-deleted HSV-1 engineered to express murine IL-12. Herein, we describe the safety and biodistribution of M032, a γ(1)34.5-deleted HSV-1 virus that expresses human IL-12 after intracerebral administration to nonhuman primates, Aotus nancymae. Cohorts were administered vehicle, 10(6), or 10(8) pfu of M032 on day 1 and subjected to detailed clinical observations performed serially over a 92-day trial. Animals were sacrificed on days 3, 31, and 91 for detailed histopathologic assessments of all organs and to isolate and quantify virus in all organs. With the possible exception of one animal euthanized on day 16, neither adverse clinical signs nor sex- or dose-related differences were attributed to M032. Elevated white blood cell and neutrophil counts were observed in virus-injected groups on day 3, but no other significant changes were noted in clinical chemistry or coagulation parameters. Minimal to mild inflammation and fibrosis detected, primarily in meningeal tissues, in M032-injected animals on days 3 and 31 had mostly resolved by day 91. The highest viral DNA levels were detected at the injection site and motor cortex on day 3 but decreased in central nervous system tissues over time. These data demonstrate the requisite safety of intracerebral M032 administration for consideration as a therapeutic for treating malignant brain tumors. |
| Databáze: | OpenAIRE |
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